2-substituted alkoxy-3-substituted-pyrazines

ABSTRACT

A compound of the formula ##STR1## wherein Q is --CO-- or --CH 2  --, R is hydroxyl, lower alkoxy, halogen, --NH-lower alkylene-OH, --NH-lower alkylene-arylthio, --NH-lower alkylene-halogen, ##STR2## in which ##STR3## is dilower alkylamino, cycloalkylamino, morpholino, ##STR4## in which R 9  is hydrogen, lower alkyl or aryl, R 10  is hydrogen, lower alkyl, hydroxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl or di(aryl)-lower alkyl, m is an integer from 4 to 6, n is 2 or 3, R 1  is alkyl or aryl-lower alkyl, R 2  and R 3  are each lower alkyl, or together form tetramethylene, and R 4  is hydrogen, lower alkyl or aryl, in which aryl is phenyl which is optionally substituted with a group selected from the group consisting of 1-3 halogen, nitro, lower alkyl and lower alkoxy, or a pharmaceutically acceptable salt thereof, inhibits blood platelet aggregation, has vasodilating activity and inhibits lipoperoxide generation.

FIELD OF THE INVENTION

This invention relates to novel 2-substituted alkoxy-3-substitutedpyrazines, which are useful as pharmaceuticals for treating circulatoryand metabolic disorders. The compounds of the invention are active asplatelet aggregation inhibiting, vasodilating and/or anti-lipoperoxidegenerating agents.

KNOWN PRIOR ART

Recently, a significant number of compounds having platelet aggregationinhibiting activity have been reported. Of these, the only knowncompounds having a pyrazine or 5,6,7,8-tetrahydro quinoxaline ring asthe basic structure are tetramethyl pyrazine (16th HeterocyclicChemistry Symposium (Osaka), pp. 65-68 (1984)) and 2-higher fatty acidacyloxymethyl pyrazine (Jap. Pat. Unexam. Publ. No. 59-219269).Furthermore, a compound of the formula ##STR5## wherein Z is hydrogen ormethyl, is known as an α-sympathetic nerve blocking agent (Jap. Pat.Exam. Publ. No. 48-21949). These compounds have almost no plateletaggregation inhibiting, vasodilating or antioxidant activity.

OBJECT OF THE INVENTION

It is an object of the invention to provide high quality pharmaceuticalshaving stronger inhibitory activities for platelet aggregation, in ordereffectively to treat circulation and metabolic disorders.

SUMMARY OF THE INVENTION

We have found that 2-substituted alkoxy-3-substituted pyrazines displayinhibitory action on platelet aggregation, vasodilation activity and/oranti-lipoperoxide generation, and are expected to have excellentpharmaceutical properties.

According to the present invention, a compound of the formula ##STR6##is provided, wherein Q is --CO-- or --CH₂ --, R is hydroxyl, loweralkoxy, halogen, -NH-lower alkylene-OH, -NH-lower alkylene-arylthio,-NH-lower alkylene-halogen, ##STR7## in which ##STR8## is diloweralkylamino, cycloalkylamino, morpholino, ##STR9## in which R₉ ishydrogen, lower alkyl or aryl, R₁₀ is hydrogen, lower alkyl,hydroxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl or di(aryl)-loweralkyl, m is an integer from 4 to 6, n is 1 or 2, R₁ is alkyl oraryl-lower alkyl, R₂ and R₃ are each lower alkyl, or together formtetramethylene, and R₄ is hydrogen, lower alkyl or aryl, in which arylis phenyl which is optionally substituted with a group selected from thegroup consisting of 1-3 halogen, nitro, lower alkyl and lower alkoxy, ora pharmaceutically acceptable salt thereof.

Compound [1] can be provided in salt form. The salts must bepharmacologically acceptable non-toxic salt thereof. Examples of suchsalts are salts of an inorganic acid such as hydrochloric, sulfuric, orphosphoric, and salts of an organic acid such as acetic, propionic,butyric, glycolic, gluconic, malic, tartaric, succinic, mandelic,aspartic, glutamic, methanesulfonic or toluenesulfonic. Salts of otherknown acids can be used as well.

Compound [1] can be produced by the following processes:

Process A:

A process for the production of compound [1] wherein Q is --CO-- and Ris lower alkoxy (hereinafter designated as compound [1a]):

The above compound [1a] can be produced by reacting a compound of theformula ##STR10## wherein M is alkali metal, and R₁, R₂ and R₃ have thesame meanings hereinbefore, with an α-halogen-carboxylate ester of theformula ##STR11## wherein X is halogen, R₁₁ is lower alkyl and R₄ hasthe same meaning hereinbefore, in an organic solvent.

The above compound [3] can be obtained by dissolving a compound of theformula ##STR12## wherein R₁, R₂ and R₃ have the same meaningshereinbefore, in methanol containing alkali metal methylate anddistilling off methanol in vacuo.

The above compound [2] can be expressed as a tautomer of a compound ofthe formula ##STR13## wherein R₁, R₂ and R₃ have the same meaningshereinabove.

In compound [2] above, R₁ is alkyl or aryl-lower alkyl. "Alkyl", as usedabove, is defined as saturated or unsaturated C₁₋₂₀ alkyl, which may bebranched or unbranched. Examples are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, heptyl,octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecylor hexadecyl, "Optionally substituted phenyl", as used above, is definedas phenyl or phenyl substituted with C₁₋₃ lower alkyl, halogen, nitro,or lower alkxoy. Aryl-lower alkyl, as used above, is defined as phenylor phenyl substituted with 1-3 halogen, nitro, lower alkyl or loweralkoxy, in which lower alkyl means C₁₋₄ alkyl such as methyl, 1-ethyl,2-ethyl, 3-propyl or 1-propyl. Examples are benzyl, p-chlorobenzyl,2-phenylethyl and 1-phenylethyl.

In compound [2] above, R₂ and R₃ are each lower alkyl, or together formtetramethylene. The lower alkyl can be C₁₋₄ alkyl such as methyl, ethyor propyl. Among the class of compounds [2], some examples have beenreported. These compounds can be produced by a process or an improvementthereto as disclosed in J. Am. Chem. Soc., 71: 78-81 (1949) and ibid.74: 1580-1583 (1952). Novel derivatives thereof can also be producedaccording to the methods described in the above references. The compound[2] wherein R₂ and R₃ together form tetramethylene of the formula##STR14## wherein R₁ has the same meaning hereinabove,hexahydroquinoxaline derivatives, is produced by the process, in whichan α-amino acidamide of the formula ##STR15## wherein R₁ has the samemeaning hereinabove, is reacted with 1,2-cyclohexanedione in an alkalinemedium.

The reaction of the above α-amino acidamide or a salt thereof with1,2-cyclohexanedione proceeds in an organic solvent, for example a loweralcohol such as methanol or ethanol. The condensation reaction proceedspreferably below 0° C. at first; however, as the reaction proceeds, itcan be effected at room temperature. The progress of the reaction can bechecked by thin layer chromatography (hereinafter TLC) or highperformance liquid chromatography (hereinafter HPLC) and is terminatedupon reaching maximum production.

Isolation of the product [2'] can be performed by neutralizing thereaction mixture with an acid such as hydrochloric acid or sulfuricacid, thereafter extracting with water immiscible organic solvent suchas chloroform under weakly alkaline conditions, and recrystallizing froman organic solvent such as acetone.

The thus-obtained product [2'] can be purified if necessary, by columnchromatography using silica-gel, active alumina or an adsorption resin.

The group R₄ in the above α-halogenocarboxylate ester [4] is defined ashydrogen, lower alkyl or aryl. Examples of lower alkyl are C₁₋₄ alkylssuch as methyl, ethyl or propyl, and that of aryl are phenyl optionallysubstituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy.

The group R₉ in the above ester [4] is C₁₋₄ alkyl such as methyl, ethylor propyl and the group X is halogen, such as chlorine, bromine oriodine.

The reaction of the compound [3] with an α-halogeno carboxylate ester[4] is in general effected in an organic solvent such asdimethylforamide while heating. Isolation of the product [1a] can beperformed by distilling off the reaction solvent and extracting theresidue with a water-immiscible organic solvent such as benzenechloroform.

Process B:

A process for the production of compound [1] wherein Q is --CO-- and Ris hydroxyl (hereinafter compound [1b]):

Compound [1b] can be produced by de-esterifying the above compound [1a]by any known de-esterification procedure. For example, compound [1a] ishydrolyzed by alkali hydroxide such as KOH or NaOH, and in case anyunreacted compound [1a] remains, after removing the same by extractingwith a water-immiscible organic solvent such as chloroform, the reactionmixture is neutralized with an acid and the precipitated product [1b] isfiltered or extracted with a water-immiscible organic solvent.

Process C:

A process for the production of compound [1] wherein Q is --CO-- and Ris -NH-lower alkylene-OH or ##STR16## (hereinafter compound [1c]):

Compound [1c] can be produced by reacting an amine of the formula

    H--R'                                                      [5]

wherein R' is -NH-lower alkylene-OH or ##STR17## in which ##STR18## isdi-lower alkylamino, cycloalkylamino morpholino, ##STR19## loweralkylene-aryl, wherein R₉, R₁₀, aryl, m and n have the same meaningshereinbefore, with a compound [1b] or its reactive derivatives forN-acylation.

In the group R' in the above amine [5] the lower akylene moiety isdefined as straight or branched C₁₋₄ lower alkylene.

Examples of lower alkylene are methylene, ethylene, methylmethylene,propylene, 1-methylethylene, ethyl-methylene butylene, isobutylene orsec-butylene; C₁₋₃ is preferred.

Di-lower alkylamino in the above ##STR20## is diakylamino of C₁₋₄ alkylsuch as dimethylamino, diethylamino or dipropylamino.

The above cycloalkylamino is cycloalkylamino of C₅₋₈, cycloalkyl such ascyclopentylamino, cyclohexyamino or cycloheptylamino.

The ring ##STR21## in the above ##STR22## wherein m is an integer of4-6, is defined as pyrrolidine, piperidine or a hexamethyleneimine ring,R₉ means hydrogen, lower alkyl or aryl. "Lower alkyl" means branched orunbranched C₁₋₄ alkyl. "Aryl" as used above means phenyl or phenylsubstituted with 1-3 halogen, nitro, lower alkyl or lower alkoxy.

The group R₁₀ in the above ##STR23## is defined as hydrogen, loweralkyl, hydroxy-lower alkyl, aryl, hydroxy-lower alkoxy-lower alkyl ordi(aryl)-lower alkyl. Examples of the above alkyl are branched orunbranched C₁₋₄ alkyl such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl and t-butyl. Examples of the above hydroxy-loweralkyl are hydroxyalkyl of C₁₋₄ such as hydroxymethyl, 2-hydroxyethyl or3-hydroxypropyl. Examples of hydroxy-lower alkoxy-lower alkyl arehydroxy alkoxy alkyl comprising alkoxy which is C₁₋₄ lower alkoxy andalkyl which is C₁₋₄ lower alkyl, for example hydroxymethoxymethyl,(2-hydroxyethoxy) methyl, 2-(2-hydroxyethoxy) ethyl or2-(hydroxymethoxy) ethyl. The group "aryl" in the above di-(aryl)-loweralkyl is phenyl optionally substituted with 1-3 halogen, nitro, loweralkyl or lower alkoxy, and the group "lower alkyl" hereinabove is C₁₋₄alkyl such as methyl or ethyl. An example of di-(aryl)-lower alkyl isdiphenylmethyl.

The ring of the group ##STR24## in the above ##STR25## wherein n is 2 or3, is piperazine or homopiperazine. A lower alkylene bound to the abovering is defined hereinabove and is branched or unbranched C₁₋₄ alkylene.

Examples of aryl are phenyl or phenyl substituted with 1-3 halogen,nitro, lower alkyl or lower alkoxy, such as phenyl, tolyl, xylyl, p(m oro)-chlorophenyl, p(m or o)-fluorophenyl, p(m or o)-bromophenyl,2,4(2,3-, 3,4-, 2,5-, 3,5- or 2,6-)dichlorophenyl, p(m oro)-nitrophenyl, p(m or o)-methoxyphenyl, 2,4(2,3-, 3,4-, 2,5-, 3,5- or2,6)-dimethoxyphenyl.

Accordingly, specific examples of the amine [5] are dimethylamine,diethylamine, 2-hydroxyethylamine, cyclohexylamine, morpholine,pyrrolidine, piperizine, hexamethyleneimine, 4-methylpiperizine,4-phenylpiperazine, piperazine, 4-methylpiperazine, 4-ethylpiperazine,4-propylpiperazine, 4-butylpiperazine, 4-(2-hydroxyethyl)-piperazine,4-[2-(2-hydroxyethoxy)ethyl]-piperazine, 4-benzylpiperazine,4-(o-chlorobenzyl)-piperazine, 4-(p-chlorobenzyl)-piperazine,4-(2,4-dichlorobenzyl)-piperazine, 4-(p-nitrobenzyl)-piperazine,4-(m-nitrobenzyl)-piperazine, 4-(o-nitrogenzyl)-piperazine,4-(p-methoxybenzyl)-piperazine, 4-(methylbenzyl)-piperazine,4-(diphenylmethyl)-piperazine, 4-benzyl-homopiperazine,4-(p-methylbenzyl)-homopiperazine, 4-(p-chlorobenzyl)-homopiperazine,4-(p-fluorobenzyl)-homopipeazine, 4-(p-nitrobenzyl)-homopiperazine and4-(p-methoxybenzyl)-homopiperazine.

The reaction of the above amine [5] and the compound [1b] or itsreaction derivative ordinarily proceeds by mixed anhydride methodreacting the compound [1b] and amine [5] with pivaloyl chloride in thepresence of a tertiary amine such as tetrahydrofuran.

The resulting compound [1f] can be isolated by pouring the reactionmixture into dilute aqueous alkali and extracting with awater-immiscible organic solvent such as benzene or chloroform.

In the above reaction, when piperazine is used as amine [5], a compound[1c], wherein R is ##STR26## in which R₁, R₂, R₃ and R₄ have the samemeanings hereinbefore, is produced depending on a ratio of piperazineused.

Process D:

A process for the production of the compound [1] wherein Q is --CO-- andR is NH-lower alkylene-halogen (hereinafter compound [1d]):

Compound [1d] can be produced by N-acylating a compound of the formula

    X-lower alkylene-NH.sub.2                                  [6]

wherein X is halogen and lower alkyl has the same meaning hereinabove,with compound [1b] or a reactive derivative thereof.

"Lower alkylene" in the above amine [6] means, as defined hereinbefore,branched or unbranched C₁₋₄ alkylene, such as methylene, ethylene,methylmethylene, propylene, 1-methylethylene, ethylmethylene, butylene,isobutylene or sec-butylene, and --(CH₂)₁₋₃ is preferred.

Examples of the above amine [6] are 2-chloroethylamine and2-bromoethylamine.

The reaction of the above amine [6] with the compound [1b] or itsreactive derivative is performed in the same way as in the process Chereinabove to produce the compound [1d].

Process E:

A process for the production of compound [1] wherein Q is --CO-- and Ris ##STR27## (hereinafter compound [1e]):

Compound [1e] can be produced by aminating the above compound [1d] withan amino of the formula ##STR28## wherein ##STR29## has the has the samemeaning hereinbefore.

The group ##STR30## in the above amine [7] has the same meaning as##STR31## as defined in the above amine [5], and the group aryl asdefined in the above ##STR32## means phenyl or phenyl substituted with1-3 halogen, nitro, lower alkyl or lower alkoxy.

Examples of amine [7] are the amine [5] hereinbefore and4-phenylpiperazine, 4-(o-chlorophenyl)-piperazine,4-(p-chlorophenyl)-piperazine, 4-(p-methoxyphenyl)-piperazine,4-(m-methoxyphenyl)-piperazine or 4-(m-methoxyphenyl)-piperazine.

The above amination reaction can be effected in an inert organic solventsuch as benzene in the presence of a tertiary organic amine such astriethylamine. Isolation of the product [1d] can be performed by pouringthe reaction mixture into dilute aqueous alkali and extracting with awater-immiscible organic solvent such as chloroform.

Process F:

A process for the production of compound [1] wherein Q is --CH₂ -- and Ris -NH-lower alkylene-arylthio (hereinafter compound [1f]):

The above compound [1f] can be produced by thioetherification of theabove compound [1d] with aryl-thiol [8].

Aryl in the above aryl-thiol [8] means phenyl or phenyl substituted with1-3 halogen, nitro, lower alkyl or lower alkoxy, such as thiophenol.

The above thio-etherification can be effected in a reaction solvent suchas dimethylformamide in the presence of an alkali such as potassiumcarbonate or sodium carbonate. Isolation of the compound [1f] can beperformed by removing the reaction solvent and extracting with awater-immiscible organic solvent such as chloroform in a dilute aqueousalkali.

Process G:

A process for the production for compound [1] wherein Q is --CH₂ -- andR is hydroxyl (hereinafter compound [1g]):

Compound [1g] can be produced by reducing the above compound [1a] withalkali borohydride in lower alcohol with heating.

Isolation of the product [1g] can be performed by removing the organicsolvent from the reaction, adding water to the residue and extractingwith a water-immiscible organic solvent such as chloroform.

Process H:

A process for the production of compound [1] wherein Q is --CH₂ -- and Ris halogen (hereinafter compound [1h]):

Compound [1h] can be produced by halogenating the above compound [1g]with a halogenating agent in a reaction solvent.

The said halogenating agent may be any known halogenating agent.Conventional chlorination reagents such as SOCl₂, PCl₅ and POCl₃ can beused. The halogenation reaction can be effected, in general, in an inertorganic solvent such as chloroform. The reaction proceeds at roomtemperature. Isolation of the product [1h] can be performed by adding awater-immiscible organic solvent such as chloroform, washing with diluteaqueous alkali, dehydrating the organic layer and removing the solventtherefrom.

The resulting compound [1h] can be used without purification, as bysilica-gel column chromatography, to derive compound [1j] below fromcompound [1h].

Process J:

A process for production of compound [1] wherein Q is --CH₂ -- and R is

                                      TABLE 26                                    __________________________________________________________________________    physical properties of 2-hydroxy-3-substituted-5,6,7,8-tetrahydroquinoxaki    ne                                                                             ##STR33##                                                                    R.sub.1 NMR (CDCl.sub.3 φ, inner standard TMS) δ ppm                                                         MASS                                 __________________________________________________________________________    Me      78-1.84 (4H, m), 2.42 (3H, s), 2.66 (4H, m), 13.05 (1H, br,                                                    165                                  Et      1.25 (3H, t), 1.7-1.9 (4H, m), 2.5-2.8 (4H, m), 2.80 (2H, q),                 13.06 (1H,                       179                                          br, s)                                                                Pro     1.00 (4H, t), 1.55 (6H, m), 2.67-2.83 (6H, m), 13.09 (1H, br,                                                  193                                  iso-Pro 1.24 (3H×2, d×2, J=6.8), 1.7-2.0 (4H, m), 2.5-2.8                 (4H, m), 3.41 (1H,               193                                          sept, J=6.8), 12.9 (1H, br, s)                                        Bu      0.94 (3H, t), 1.24-2.00 (8H, m), 2.55-2.85 (6H, m), 12.99 (1H,                br, s)                           207                                  iso-Bu  0.96 (3H×2, d), 1.6-2.0 (4H, m), 2.0-2.4 (1H, m), 2.5-2.8               (6H, m)                          207                                  sec-Bu  0.96 (3H×2, d×2, J=6.7), 1.6-2.2 (5H, m), 2.5-2.8                 (6H, m)                          207                                  (CH.sub.2).sub.4 CH.sub.3                                                             0.90 (3H, t, J=6.3), 1.2-1.5 (4H, m), 1.5-1.9 (6H, m), 2.5-2.9                (6H, m)                          221, 164                             (CH.sub.2).sub.5 CH.sub.3                                                             0.88 (3H, t, J=7.9), 1.1-1.5 (6H, m), 1.5-2.0 (6H, m), 2.4-2.9                (6H, m)                          235                                  (CH.sub.2).sub.6 CH.sub.3                                                             0.88 (3H, t, J=7.4), 1.1-1.5 (8H, m), 1.5-2.0 (6H, m), 2.5-2.9                (6H, m)                          249, 164                             (CH.sub.2).sub.7 CH.sub.3                                                             0.88 (3H, t, J=7.5), 1.1-1.5 (10H, m), 1.5-2.0 (6H, m), 2.5-2.9               (6H, m)                          263                                  (CH.sub.2).sub.8 CH.sub.3                                                             0.88 (3H, t, J=6.2), 1.1-1.5 (12H, m), 1.5-2.0 (6H, m), 2.5-2.8               (6H, m)                          277, 164                             (CH.sub.2).sub.9 CH.sub.3                                                             0.88 (3H, t, J=6), 1.2-2.0 (20H, m), 2.5-2.9 (6H, m), 12.7 (1H,               br, s)                           291                                  (CH.sub.2).sub.11 CH.sub.3                                                            0.88 (3H, t, J=6), 1.1-1.9 (24H, m), 2.4-2.8 (6H,                                                              319, 164                             (CH.sub.2).sub.13 CH.sub.3                                                            0.88 (3H, t, J=6), 1.1-1.9 (28H, m), 2.5-2.8 (6H,                                                              347, 164                             (CH.sub.2).sub.15 CH.sub.3                                                            0.88 (3H, t, J=6), 1.1- 1.9 (32H, m), 2.5-1.8 (6H,                                                             375, 164                             CH.sub.2 Ph                                                                           1.6-2.0 (4H, m), 2.4-2.7 (4H, m), 4.02 (2H, s), 7.0-7.4 (4H,                                                   241                                  CH.sub.2 CH.sub.2 Ph                                                                  1.6-2.0 (4H, m), 2.5-2.8 (4H, m), 3.06 (2H×2, s), 7.1-7.3               (5H, s), 12.9                    255                                          (1H, br, s)                                                           __________________________________________________________________________     ##STR34##     (hereinafter compound [1j]):

A compound [1j] can be produced by aminating compound [1h] above withthe amine [5] in a reaction solvent with heating.

The above amination reaction can be effected in an organic solvent suchas benzene with heating.

In the above reaction, co-generated acid can be removed by an acidbinder, for example a known tertiary organic amine such astriethylamine.

The product [1j] can be isolated by pouring the reaction mixture intodilute aqueous alkali and extracting with a water-immiscible organicsolvent such as benzene or chloroform.

The thus-obtained compound [1] is purified, if required, by columnchromatography using silica gel, activated alumina or an adsorptionresin with an elution solvent such as chloroform-methanol orbenzene-ethyl acetate.

A compound [1] is generally produced in the form of its free base, itcan also be produced in the form of a conventional salt thereof. Forexample, a hydrochloride can be prepared by dissolving a compound [1] ina lower alcohol such as methanol or ethanol, adding a slight molarexcess of hydrochloric acid, and isolating the precipitated material, orif not precipitated, by adding ether therein to precipitate the same.The molar ratio of hydrochloric acid may be different according to thespecific compound [1].

Examples of the compound [1] of the present invention are set forth inTables 1 and 2.

                                      TABLE 1                                     __________________________________________________________________________     ##STR35##                                                                    Compound No.                                                                          R.sub.1                                                                            R.sub.2                                                                          R.sub.3                                                                          R.sub.4                                                                          Q    R                                                  __________________________________________________________________________    034     Me   Me Me H  CO   OMe                                                035     Me   Me Me Me CO   OMe                                                036     Me   Me Me Ph CO   OMe                                                037     Me   Me Me H  CO   OH                                                 038     Me   Me Me Me CO   OH                                                 039     Me   Me Me Ph CO   OH                                                 066     Me   Me Me H  CO                                                                                  ##STR36##                                         067     Me   Me Me H  CO                                                                                  ##STR37##                                         068     Me   Me Me H  CO                                                                                  ##STR38##                                         069     Me   Me Me H  CO   NHCH.sub.2 CH.sub.2OH                              070     Me   Me Me H  CO                                                                                  ##STR39##                                         071     Me   Me Me H  CO   NHCH.sub.2 CH.sub.2NMe.sub.2                       072     Me   Me Me H  CO   NHCH.sub.2 CH.sub.2SPh                             073     Me   Me Me H  CO                                                                                  ##STR40##                                         074     Me   Me Me H  CO                                                                                  ##STR41##                                         075     Me   Me Me H  CO                                                                                  ##STR42##                                         076     Me   Me Me H  CO                                                                                  ##STR43##                                         103     Me   Me Me H  CO                                                                                  ##STR44##                                         105     Me   Me Me H  CO                                                                                  ##STR45##                                         135     Me   Me Me H  CO                                                                                  ##STR46##                                         136     Me   Me Me H  CO                                                                                  ##STR47##                                         137     Me   Me Me H  CO                                                                                  ##STR48##                                         341     Et   Me Me Ph CO                                                                                  ##STR49##                                         342     Et   Me Me Ph CO                                                                                  ##STR50##                                         343     Et   Me Me Ph CO                                                                                  ##STR51##                                         344     Et   Me Me Ph CO                                                                                  ##STR52##                                         345     Et   Me Me Ph CO                                                                                  ##STR53##                                         346     Et   Me Me Ph CO                                                                                  ##STR54##                                         347     Et   Me Me Ph CO                                                                                  ##STR55##                                         348     Et   Me Me Ph CO                                                                                  ##STR56##                                         376     CH.sub.2 Ph                                                                        Et Et H  CO                                                                                  ##STR57##                                         377     CH.sub.2 Ph                                                                        Et Et H  CO                                                                                  ##STR58##                                         379     "    Et Et H  CO                                                                                  ##STR59##                                         381     "    Et Et H  CO                                                                                  ##STR60##                                         382     "    Et Et H  CO                                                                                  ##STR61##                                         491     Et   Me Me H  CH.sub.2                                                                            ##STR62##                                         492     Et   Me Me H  CH.sub.2                                                                            ##STR63##                                         493     Et   Me Me H  CH.sub.2                                                                            ##STR64##                                         494     Et   Me Me H  CH.sub.2                                                                            ##STR65##                                         495     Et   Me Me H  CH.sub.2                                                                            ##STR66##                                         496     Et   Me Me H  CH.sub.2                                                                            ##STR67##                                         497     Et   Me Me H  CH.sub.2                                                                            ##STR68##                                         498     Et   Me Me H  CH.sub.2                                                                            ##STR69##                                         499     Et   Me Me H  CH.sub.2                                                                            ##STR70##                                         500     Et   Me Me H  CH.sub.2                                                                            ##STR71##                                         501     Et   Me Me H  CH.sub.2                                                                            ##STR72##                                         502     Et   Me Me H  CH.sub.2                                                                            ##STR73##                                         503     Et   Me Me H  CH.sub.2                                                                            ##STR74##                                         504     Et   Me Me H  CH.sub.2                                                                            ##STR75##                                         511     CH.sub.2 Ph                                                                        Me Me H  CH.sub.2                                                                            ##STR76##                                         512     "    Me Me H  CH.sub.2                                                                            ##STR77##                                         516     "    Me Me H  CH.sub.2                                                                            ##STR78##                                         536     Me   Me Me H  CH.sub.2                                                                            ##STR79##                                         537     Me   Me Me H  CH.sub.2                                                                            ##STR80##                                         538     Me   Me Me H  CH.sub.2                                                                            ##STR81##                                         539     Me   Me Me H  CH.sub.2                                                                            ##STR82##                                         540     Me   Me Me H  CH.sub.2                                                                            ##STR83##                                         541     Me   Me Me H  CH.sub.2                                                                            ##STR84##                                         544     iso-Pro                                                                            Me Me H  CH.sub.2                                                                            ##STR85##                                         546     "    Me Me H  CH.sub.2                                                                            ##STR86##                                         547     "    Me Me H  CH.sub.2                                                                            ##STR87##                                         550     "    Et Et H  CH.sub.2                                                                            ##STR88##                                         551     "    Et Et H  CH.sub.2                                                                            ##STR89##                                         552     iso-Pro                                                                            Et Et H  CH.sub.2                                                                            ##STR90##                                         553     "    Et Et H  CH.sub.2                                                                            ##STR91##                                         556     iso-Bu                                                                             Et Et H  CH.sub.2                                                                            ##STR92##                                         558     "    Et Et H  CH.sub.2                                                                            ##STR93##                                         648     Me   Me Me H  CO   NHCH.sub.2 CH.sub.2Br                              649     Me   Me Me H  CO   NHCH.sub.2 CH.sub.2Cl                              650     Me   Me Me H  CO   NHCH.sub.2 CH.sub.2C.sub.6 H.sub.11                651     Et   Me Me Ph CO   OMe                                                652     Et   Me Me Ph CO   OH                                                 653     Et   Me Me Ph CO   NHCH.sub.2 CH.sub.2Cl                              654     CH.sub.2 Ph                                                                        Et Et H  CO   OMe                                                655     "    Et Et H  CO   OH                                                 656     "    Et Et H  CO   NHCH.sub.2 CH.sub.2Cl                              657     "    Et Et H  CO                                                                                  ##STR94##                                         658     "    Et Et H  CO                                                                                  ##STR95##                                         662     Et   Me Me H  CO   OMe                                                663     CH.sub.2 Ph                                                                        Me Me H  CO   OMe                                                664     iso-Pro                                                                            Me Me H  CO   OMe                                                665     "    Et Et H  CO   OMe                                                666     iso-Pro                                                                            Et Et H  CO   OMe                                                679     Me   Me Me H  CH.sub.2                                                                           OH                                                 680     Et   Me Me H  CH.sub.2                                                                           OH                                                 681     CH.sub.2 Ph                                                                        Me Me H  CH.sub.2                                                                           OH                                                 682     iso-Pro                                                                            Me Me H  CH.sub.2                                                                           OH                                                 683     "    Et Et H  CH.sub.2                                                                           OH                                                 684     iso-Bu                                                                             Et Et H  CH.sub.2                                                                           OH                                                 697     iso-Pro                                                                            Me Me H  CH.sub.2                                                                            ##STR96##                                         810     Me   Me Me H  CH.sub.2                                                                            ##STR97##                                         812     Et   Me Me H  CH.sub.2                                                                            ##STR98##                                         814     iso-Pro                                                                            Me Me H  CH.sub.2                                                                            ##STR99##                                         822     Me   Me Me H  CH.sub.2                                                                            ##STR100##                                        825     iso-Pro                                                                            Me Me H  CH.sub.2                                                                            ##STR101##                                        826     iso-Pro                                                                            Et Et H  CH.sub.2                                                                            ##STR102##                                        834     iso-Pro                                                                            Me Me H  CH.sub.2                                                                            ##STR103##                                        842     Me   Me Me H  CH.sub.2                                                                           NEt.sub.2                                          844     Et   Me Me H  CH.sub.2                                                                           NEt.sub.2                                          846     iso-Pro                                                                            Me Me H  CH.sub.2                                                                           NEt.sub.2                                          848     iso-Pro                                                                            Et Et H  CH.sub.2                                                                           NEt.sub.2                                          __________________________________________________________________________     Me; methyl                                                                    Et; ethyl                                                                     Pro; propyl                                                                   Bu; butyl                                                                     Ph; benzene ring                                                              ( ); position of substituent                                                  ##STR104##                                                                    ##STR105##                                                                    ##STR106##                                                                    -                                                                             ##STR107##                                                                    -                                                                        

                                      TABLE 2                                     __________________________________________________________________________     ##STR108##                                                                   Compound No.                                                                          R.sub.1 Q    R                                                        __________________________________________________________________________    368     CH.sub.2 Ph                                                                           CO                                                                                  ##STR109##                                              369     "       CO                                                                                  ##STR110##                                              370     "       CO                                                                                  ##STR111##                                              371     "       CO                                                                                  ##STR112##                                              372     "       CO                                                                                  ##STR113##                                              373     "       CO                                                                                  ##STR114##                                              517     Bu      CH.sub.2                                                                            ##STR115##                                              518     Bu      CH.sub.2                                                                            ##STR116##                                              519     Bu      CH.sub.2                                                                            ##STR117##                                              520     Bu      CH.sub.2                                                                            ##STR118##                                              521     Bu      CH.sub.2                                                                            ##STR119##                                              522     Bu      CH.sub.2                                                                            ##STR120##                                              559     (CH.sub.2).sub.4 CH.sub.3                                                             CH.sub.2                                                                            ##STR121##                                              560     (CH.sub.2).sub.4 CH.sub.3                                                             CH.sub.2                                                                            ##STR122##                                              561     "       CH.sub.2                                                                            ##STR123##                                              562     "       CH.sub.2                                                                            ##STR124##                                              563     "       CH.sub.2                                                                            ##STR125##                                              564     (CH.sub.2).sub.5 CH.sub.3                                                             CH.sub.2                                                                            ##STR126##                                              565     "       CH.sub.2                                                                            ##STR127##                                              567     "       CH.sub.2                                                                            ##STR128##                                              568     "       CH.sub.2                                                                            ##STR129##                                              569     "       CH.sub.2                                                                            ##STR130##                                              570     "       CH.sub.2                                                                            ##STR131##                                              571     (CH.sub.2).sub.6 CH.sub.3                                                             CH.sub.2                                                                            ##STR132##                                              572     (CH.sub.2).sub.7 CH.sub.3                                                             CH.sub.2                                                                            ##STR133##                                              573     "       CH.sub.2                                                                            ##STR134##                                              574     "       CH.sub.2                                                                            ##STR135##                                              575     "       CH.sub.2                                                                            ##STR136##                                              576     "       CH.sub.2                                                                            ##STR137##                                              577     (CH.sub.2).sub.7 CH.sub.3                                                             CH.sub.2                                                                            ##STR138##                                              578     "       CH.sub.2                                                                            ##STR139##                                              579     (CH.sub.2).sub.8 CH.sub.3                                                             CH.sub.2                                                                            ##STR140##                                              580     "       CH.sub.2                                                                            ##STR141##                                              581     "       CH.sub.2                                                                            ##STR142##                                              582     "       CH.sub.2                                                                            ##STR143##                                              583     "       CH.sub.2                                                                            ##STR144##                                              584     "       CH.sub.2                                                                            ##STR145##                                              585     (CH.sub.2).sub.9 CH.sub.3                                                             CH.sub.2                                                                            ##STR146##                                              586     "       CH.sub.2                                                                            ##STR147##                                              587     "       CH.sub.2                                                                            ##STR148##                                              588     "       CH.sub.2                                                                            ##STR149##                                              589     "       CH.sub.2                                                                            ##STR150##                                              590     "       CH.sub.2                                                                            ##STR151##                                              591     "       CH.sub.2                                                                            ##STR152##                                              592     "       CH.sub.2                                                                            ##STR153##                                              593     (CH.sub.2).sub.9 CH.sub.3                                                             CH.sub.2                                                                            ##STR154##                                              594     (CH.sub.2).sub.11 CH.sub.3                                                            CH.sub.2                                                                            ##STR155##                                              595     "       CH.sub.2                                                                            ##STR156##                                              596     "       CH.sub.2                                                                            ##STR157##                                              597     "       CH.sub.2                                                                            ##STR158##                                              598             CH.sub.2                                                                            ##STR159##                                              599     "       CH.sub.2                                                                            ##STR160##                                              600     (CH.sub.2).sub.13 CH.sub.3                                                            CH.sub.2                                                                            ##STR161##                                              601     "       CH.sub.2                                                                            ##STR162##                                              602     "       CH.sub.2                                                                            ##STR163##                                              603     "       CH.sub.2                                                                            ##STR164##                                              604     "       CH.sub.2                                                                            ##STR165##                                              605     "       CH.sub.2                                                                            ##STR166##                                              606     (CH.sub.2).sub.15 CH.sub.3                                                            CH.sub.2                                                                            ##STR167##                                              607     "       CH.sub.2                                                                            ##STR168##                                              608     "       CH.sub.2                                                                            ##STR169##                                              609     (CH.sub.2).sub.15 CH.sub.3                                                            CH.sub.2                                                                            ##STR170##                                              610     "       CH.sub.2                                                                            ##STR171##                                              659     CH.sub.2 Ph                                                                           CO   OMe                                                      660     "       CO    OH                                                      661     "       CO   NHCH.sub.2 CH.sub.2Cl                                    667     Bu      CO   OMe                                                      668     (CH.sub.2).sub.4 CH.sub.3                                                             CO   OMe                                                      669     (CH.sub.2).sub.5 CH.sub.3                                                             CO   OMe                                                      670     (CH.sub.2).sub.6 CH.sub.3                                                             CO   OMe                                                      671     (CH.sub.2).sub.7 CH.sub.3                                                             CO   OMe                                                      672     (CH.sub.2).sub.8 CH.sub.3                                                             CO   OMe                                                      673     (CH.sub.2).sub.9 CH.sub.3                                                             CO   OMe                                                      674     (CH.sub.2).sub.11 CH.sub.3                                                            CO   OMe                                                      675     (CH.sub.2).sub.13 CH.sub.3                                                            CO   OMe                                                      676     (CH.sub.2).sub.15 CH.sub.3                                                            CO   OMe                                                      677     Pro     CO   OMe                                                      678     sec-Bu  CO   OMe                                                      685     Bu      CH.sub.2                                                                           OH                                                       686     (CH.sub.2).sub.4 CH.sub.3                                                             CH.sub.2                                                                           OH                                                       687     (CH.sub.2).sub.5 CH.sub.3                                                             CH.sub.2                                                                           OH                                                       688     (CH.sub.2).sub.6 CH.sub.3                                                             CH.sub.2                                                                           OH                                                       689     (CH.sub.2).sub.7 CH.sub.3                                                             CH.sub.2                                                                           OH                                                       690     (CH.sub.2).sub.8 CH.sub.3                                                             CH.sub.2                                                                           OH                                                       691     (CH.sub.2).sub.9 CH.sub.3                                                             CH.sub.2                                                                           OH                                                       692     (CH.sub.2).sub.11 CH.sub.3                                                            CH.sub.2                                                                           OH                                                       693     (CH.sub.2).sub.13 CH.sub.3                                                            CH.sub.2                                                                           OH                                                       694     (CH.sub.2).sub.15 CH.sub.13                                                           CH.sub.2                                                                           OH                                                       695     Pro     CH.sub.2                                                                           OH                                                       696     sec-Bu  CH.sub.2                                                                           OH                                                       817     Bu      CH.sub.2                                                                            ##STR172##                                              830     (CH.sub.2).sub.7 CH.sub.3                                                             CH.sub.2                                                                            ##STR173##                                              837     Bu      CH.sub.2                                                                            ##STR174##                                              839     (CH.sub.2).sub.7 CH.sub.3                                                             CH.sub.2                                                                            ##STR175##                                              850     Bu      CH.sub.2                                                                           NEt.sub.2                                                851     (CH.sub.2).sub.7 CH.sub.3                                                             CH.sub.2                                                                           NEt.sub.2                                                __________________________________________________________________________     Me; methyl                                                                    Et; ethyl                                                                     Pro; propyl                                                                   Bu; butyl                                                                     Ph; benzene ring                                                              ( ): position of substituent                                                  ##STR176##                                                                    ##STR177##                                                                    ##STR178##                                                                    ##STR179##                                                               

The pharmacological activity of the present compounds [1] is illustratedbelow. All the compounds [1] used in the pharmacological tests weretested in the form of the hydrochloride salt thereof.

1. Platelet aggregation inhibition:

Sample solution containing a compound [1] (final concentration 500 or100 μM) is added to rabbit platelet plasma to which was added 10% byvolume of a 3.8% sodium citrate solution, and the mixture is incubatedat 37° C. for 3 minutes. A platelet activation factor (PAF, finalconcentration 10-50 μg/ml) or collagen (final concentration 2.5 μg/ml)is added thereto as an aggregating agent, and platelet aggregationactivity is measured with an aggregometer. The results of assays forPAF-induced aggregation are shown in Table 3, and those forcollagen-induced aggregation are shown in Table 4, which tables show thestrong platelet aggregation inhibitory activity of the compounds [1] ofthe present invention.

                  TABLE 3                                                         ______________________________________                                        Platelet aggregation inhibitory action on PAF-                                induced aggregation                                                                          concentration                                                                            inhibition ratio                                    Compound No.   (μM)    (%)                                                 ______________________________________                                        560            100        97                                                  561            100        56                                                  562            100        45                                                  565            100        94                                                  567            100        58                                                  570            100        40                                                  571            100        88                                                  573            100        86                                                  580            100        94                                                  587            100        91                                                  588            100        64                                                  595            100        85                                                  600            100        52                                                  067            300        53                                                  070            500        48                                                  135            500        77                                                  136            100        50                                                  137            100        76                                                  341            100        42                                                  342            100        43                                                  344            100        44                                                  347            100        59                                                  348            100        70                                                  502            100        81                                                  503            100        42                                                  504            100        60                                                  541            100        44                                                  550            100        56                                                  551            100        97                                                  552            100        78                                                  553            100        82                                                  556            100        51                                                  ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Platelet aggregation inhibitory action on                                     collagen-induced aggregation                                                                 concentration                                                                            inhibition ratio                                    compound No.   (μM)    (%)                                                 ______________________________________                                        573            100        58                                                  580            100        80                                                  582            100        58                                                  585            100        41                                                  587            100        79                                                  588            100        78                                                  547            100        56                                                  550            100        85                                                  556            100        40                                                  ______________________________________                                    

2. Vasodilation activity:

A dog, pretreated with morphine (1.5 mg/kg, sc) is anesthesized withurethane (450 mg/kg, iv) and α-chloralose (45 mg/kg, iv), andimmobilized in the dosal position. Right femoral arterial blood isintroduced into a left femoral artery via a perfusion pump, andSterling's resistance is connected to the exosomatic circulatory systemto perfuse blood to a left back limb at constant pressure. The perfusionpressure is set at a value slightly higher than that of the averageblood pressure of the animal. Sample (100 μg) dissolved in physiologicalsaline solution is administered to a right femoral artery, and changesin blood flow are measured. Vasodilation activity is measured as arelative activity, by defining as 100% the increased rate of blood flowwhen 30 μg papaverin is administered intra-arterially. The results areshown in Table 5, where it will be seen that the compounds [1] of thepresent invention have strong vasodilation activity.

                  TABLE 5                                                         ______________________________________                                        Vasodilation Activity                                                         compound No.  vasodilation activity (%)                                       ______________________________________                                        075           89                                                              135           242                                                             136           204                                                             137           216                                                             ______________________________________                                    

3. Antioxidant activity:

Antioxidant activity is determined according to the method of Stocks etal. [Clin. Sci. Mol. Med., 47: 215 (1974)]. Rat cerebrum is added toice-cooled 40 mM phosphate saline buffer solution (PBS) (pH 7.4, 4 mlbuffer per 1 g cerebrum), homogenized and centrifuged (1000×g, 4° C., 10min.) to obtain a supernatant solution. The supernatant solution isdiluted fivefold with the above ice-cooled PBS solution, and to a 0.9 mlaliquot thereof is added a sample containing a compound [1] (0.1 ml,final concentration 100 μM) dissolved in ethanol. The resultant mixtureis incubated at 37° C. for 15 minutes, 35% perchloric acid (0.2 ml) isadded, and the mixture is ice-cooled to stop the reaction andcentrifuged (1300×g, 4° C., 10 min.). 0.5 ml thiobarbituric acid (5g/lit. of 50% acetic acid) is added to the supernatant solution (1 ml),so as to measure its absorbancy at 532 nm. The amount of lipoperoxidethus generated is expressed as an amount of malondialdehyde. The resultsare shown in Table 6, where it will be seen that the compounds [1] ofthe present invention inhibit lipoperoxide generation.

                  TABLE 6                                                         ______________________________________                                        Antioxidant activity                                                          compound No.   inhibition ratio (%)                                           ______________________________________                                        371            49                                                             372            64                                                             373            49                                                             520            83                                                             562            65                                                             568            61                                                             569            81                                                             570            65                                                             573            56                                                             574            71                                                             575            79                                                             576            85                                                             577            71                                                             578            88                                                             580            77                                                             581            71                                                             582            82                                                             583            82                                                             584            65                                                             585            62                                                             586            68                                                             587            65                                                             588            65                                                             589            74                                                             590            74                                                             591            59                                                             592            85                                                             593            73                                                             594            58                                                             595            70                                                             596            73                                                             597            76                                                             598            88                                                             599            70                                                             600            61                                                             601            67                                                             602            64                                                             603            76                                                             607            52                                                             608            55                                                             609            61                                                             344            48                                                             345            54                                                             347            51                                                             348            62                                                             379            50                                                             382            83                                                             502            69                                                             516            75                                                             ______________________________________                                    

As explained hereinabove, a compound [1] of the present invention or itscorresponding salt inhibits platelet aggregation, has vasodilatingactivity, and/or inhibits lipoperoxide generation, and is useful inpharmaceutical form for treating circulatory and metabolic disorders.

The following examples are illustrative of the present invention but arenot to be construed as limiting.

In the examples, the Rf value of silica-gel thin layer chromatography(TLC) is either specified by or measured using the following carrier anddeveloping solvent:

Carrier: silica gel, Kieselgel 60 F₂₅₄ Art 5715 (Merck).

Developer: chloroform-methanol (20:1).

Physical properties (NMR, Mass, CI, Rf upon TLC) of the compounds [1]obtained in the following examples are shown in Tables 25-27.

Symbols for chemical structure in Tables 7-19 have the same meanings asin Table 1, and the symbols in Tables 20-24 have the same meanings as inTable 2.

EXAMPLE 1 Methyl (3,5,6-trimethylpyrazine-2-yl oxy) acetate (compound034)

Metallic sodium (1.29 g, 56 mM) was dissolved in anhydrous methanol (120ml). 2-hydroxy-3,5,6-trimethylpyrazine (7.74 g, 56 mM) was dissolvedtherein, and methanol was distilled off in vacuo to obtain sodium3,5,6-trimethyl-2-pyrazinolate which was suspended in dimethylformamide(150 ml). Methyl chloroacetate (10.85 g, 0.10M) was added thereto andthe mixture was stirred at 95-100° C. for 3 hours. The solvent wasremoved in vacuo. Dilute aqueous sodium carbonate was added to theresidue, which was then extracted twice with chloroform (200 ml), andthe extract was dried with anhydrous magnesium sulfate and concentratedin vacuo. The residue was charged on a column of silica gel (Wako PureChem. Co., C-200, 170 g) and eluted with benzene and benzene-ethylacetate (10:1) successively to obtain the product. (8.23 g, yield:70.0%).

EXAMPLE 2 Methyl α-(3,5,6-trimethylpyrazine-2-yl oxy) propionate(compound 035)

Methyl α-chloropropionate (12.25 g, 0.10 mM) was added to sodium3,5,6-trimethyl-2-pyrazinolate (8.00 g, 50 mM) suspended indimethylformamide (100 ml) and the mixture was stirred at 95°-100° C.for 7 hours. The solvent was distilled off in vacuo. Dilute aqueoussodium carbonate was added to the residue, which was then extracted oncewith chloroform (200 ml) and twice with chloroform (100 ml), and theextract was dried with anhydrous magnesium sulfate and concentrated invacuo. The residue was charged on a column of silica gel (Wako PureChem. Co., C-200, 160 g) and eluted with benzene and benzene-ethylacetate (10:1) successively to obtain the product. (8.39 g, yield:74.9%).

EXAMPLE 3 Methyl α-(3,5,6-trimethylpyrazine-2-yl oxy) phenyl acetate(compound 036)

Methyl α-bromophenyl acetate (23.0 g, 0.10 mM) was added to sodium3,5,6-trimethyl-2-pyrazinolate (8.00 g, 50 mM) suspended indimethylformamide (150 ml) and the mixture was stirred at 100° C. for 5hours. The reaction mixture was treated in the same way as in Example 2to obtain the product. (10.97 g, yield: 76.7%).

EXAMPLE 4 (3,5,6-trimethylpyrazine-2-yl oxy) acetate (compound 037)

Aqueous 1N-NaOH (80 ml) was added to compound 034 (8.40 g, 40 mM) andthe mixture was stirred for 30 minutes. 1N-HCl (80 ml) was added to thereaction mixture and the precipitated crystals were collected byfiltration to obtain a portion of the product. (3.15 g) The filtrate wasdried in vacuo and the residue was extracted with hot ethanol, then theextract was dried in vacuo to obtain the remainder of the product. (4.09g) (Total: 7.24 g, yield: 92.3%).

EXAMPLE 5 α-(3,5,6-trimethylpyrazine-2-yl oxy) propionate (compound 038)

Aqueous 1N-NaOH (80 ml) was added to compound 035 (7.81 g, 35 mM) andthe mixture was stirred for 1 hour. The reaction mixture was extractedwith chloroform to remove unreacted compound. 1N-HCl (70 ml) was addedto the aqueous layer and the mixture was concentrated in vacuo toprecipitate crystals, which were collected by filtration, washed withwater completely and dried to obtain the product. (6.66 g, yield:90.6%).

EXAMPLE 6 α-(3,5,6-trimethylpyrazine-2-yl oxy) phenyl acetate (compound039)

Aqueous 1N-NaOH (75 ml) was added to compound 036 (10.80 g, 37.7 mM)dissolved in methanol (75 ml) and the mixture was stirred for 1.5 hour.Methanol was distilled off in vacuo and the aqueous layer was washedwith chloroform. 1N-HCl (75 ml) was added to the aqueous layer which wasextracted with chloroform. The extract was dried with anhydrousmagnesium sulfate and concentrated in vacuo to obtain the product aswhite crystals. (9.89 g, yield: 96.4%)

EXAMPLES 7-12 2-(substituted carbonylmethoxy)-3,5,6-trimethylpyrazine

Triethylamine (0.70 ml, 5 mM) was added to compound 037 (0.98 g, 5 mM)dissolved in tetrahydrofuran. Pivaloyl chloride (0.16 g, 5 mM) was addeddropwise at -5° C. and the mixture was stirred for 30 minutes with icecooling. A tetrahydrofuran solution of a base (5 mM) was added dropwiseto the reaction mixture and the mixture was stirred at room temperaturefor 4 hours. The reaction mixture was concentrated in vacuo and theresidue was dried with chloroform, then concentrated in vacuo. Theresidue was charged on a column of silica gel (C-20, 60 g) and elutedwith chloroform and chloroform-methanol (200:1) successively to obtainthe compounds in Table 7.

Table 7 identifies the product, yields in weight and percentage, thebase and its amount used.

EXAMPLE 13 N-(2-bromoethyl)-(3,5,6-trimethylpyrazine-2-yl oxy) acetamide(compound 648)

Triethylamine (7.0 ml, 50 mM) was added to compound 037 (9.80 g, 50 mM)dissolved in tetrahydrofuran (100 ml) and chloroform (100 ml) insolution with bromoethylamine hydrobromide (10.30 g, 50 mM) andtriethylamine (7.7 ml, 55 mM) was added dropwise at -5° C., then themixture was stirred for 4 hours with ice cooling. The reaction mixturewas concentrated in vacuo, the residue was dissolved in chloroform andwashed with dilute aqueous potassium carbonate. The aqueous layer wasextracted with chloroform. The organic layer was combined, dried withanhydrous magnesium sulfate, and concentrated in vacuo. The residue wascharged on a column of silica gel (Chlodil, 250 g), and elutedsuccessively with chloroform and chloroform-methanol (500:1) to obtainthe product (6.92 g)

EXAMPLE 14 N-(2-chloroethyl)-(3,5,6-trimethylpyrazine-2-yl oxy)acetamide (compound 649)

Triethylamine (3.50 ml, 25 mM) was added to compound 037 (4.90 g, 25 mM)dissolved in tetrahydrofuran (50 ml) and pivaloyl chloride (3.05 g, 25mM) was added dropwise at -5° C., then the mixture was stirred for 30minutes. Chloroform (50 ml) in solution with 2-chloroethylaminehydrochloride (2.90 g, 25 mM) and triethylamine (3.9 ml, 28 mM) wasadded dropwise thereto, then the mixture was stirred for 4 hours whileslowly reaching room temperature. The reaction mixture was concentratedin vacuo, the residue was dissolved in chloroform and washed with diluteaqueous potassium carbonate. The aqueous layer was extracted withchloroform. The organic layer was combined, dried with anhydrousmagnesium sulfate, and concentrated in vacuo. The residue was charged ona column of silica gel (C-200, 40 g), and eluted successively withchloroform and chloroformmethanol (20:1) to obtain the product (5.66 g,yield: 7.5%).

EXAMPLES 15-21 N-(2-substituted ethyl)-(3,5,6-trimethylpyrazine-2-yloxy) acetamide

Benzene (20 ml) in solution with compound 648 (0.91 g, 3.0 mM),triethylamine (0.84 ml) and a base was refluxed. The reaction mixturewas washed with dilute aqueous potassium carbonate, and the aqueouslayer was extracted with chloroform. The organic layers (benzene andchloroform) was combined, dried with anhydrous magnesium sulfate, andconcentrated in vacuo. The residue was charged on a column of silica gel(C-200, 65 g) and eluted successively with chloroform andchloroform-methanol to obtain the compounds in Table 8.

Table 8 shows the reflux time, yield in weight and percentage, the baseand its amount used and the ratio of chloroform-methanol mixture used ineach of the above examples.

EXAMPLE 22

N-(2-phenylthioethyl)-(3,5,6-trimethylpyrazine-2-yl oxy) acetamide(compound 072)

Thiophenol (0.60 g, 5.4 mM) and potassium carbonate (0.75 g, 5.4 mM)were added to compound 648 (0.91 g, 3.0 mM) dissolved indimethylformamide (10 ml) and the mixture was stirred for 2 hours atroom temperature. The reaction mixture was concentrated in vacuo, theresidue was dissolved in chloroform and washed with dilute aqueouspotassium carbonate. The aqueous layer was further extracted withchloroform. The combined organic layer was chromatographed by elutingsuccessively with benzene and benzene-ethyl acetate (10:1) to obtain theproduct (0.35 g, yield: 35.2%).

EXAMPLES 23-25 N-(2-substituted ethyl)-(3,5,6-trimethylpyrazine-2-yloxy) acetamide

Benzene (25 ml) in solution with compound 649 (0.98 g, 4 mM),triethylamine (1.14 ml) and a base was refluxed. The reaction mixturewas washed with dilute aqueous potassium carbonate, and the aqueouslayer was further extracted with chloroform. The organic layers (benzeneand chloroform) were combined, dried with anhydrous magnesium sulfate,and concentrated in vacuo. The residue was charged on a column of silicagel (C-200, 80 g) and eluted successively with chloroform andchloroform-methanol to obtain the compounds in Table 9.

Table 9 shows the identity of the base and its amount used, the refluxtime, the ratio of chloroform-methanol mixture used, the products andthe yield in weight and percentage, in each of the above examples.

EXAMPLE 26 Methyl α-(3-ethyl-5,6-dimethylpyrazine-2-yl oxy) phenylacetate (compound 651)

A solution (12.5 ml) of 4N-CH₃ ONa/methanol was added to a solution of2-hydroxy-3-ethyl-5,6-dimenthylpyrazine (7.60 g, 50 mM) in anhydrousmethanol (100 ml), and methanol was distilled off in vacuo. The residuewas dissolved in dimethylformamide (150 ml). Methyl α-bromophenylacetate (11.5 g, 50 mM) was added thereto, and the mixture was stirredat 100° C. for 5 hours. The reaction mixture was concentrated in vacuo.The residue was dissolved in chloroform, and washed with dilute aqueouspotassium carbonate. The aqueous layer was further extracted twice withchloroform. The organic layers were combined, dried with anhydrousmagnesium sulfate, and concentrated in vacuo. The residue was charged ona column of silica gel (C-200, 170 g) and eluted successively withbenzene and benzene-ethyl acetate (50:1) to obtain the product. (10.42g, yield: 69.5%).

EXAMPLE 27 α-(3-ethyl-5,6-dimethylpyrazine-2-yl oxy) phenyl acetate(compound 652)

Aqueous 2N-NaOH (25.7 ml) was added to compound 651 (7.72 g, 25.7 mM)dissolved in methanol (30 ml) and the mixture was stirred for 4.5 hoursat room temperature. The reaction mixture, to which 2N-HCl (25.7 ml) wasadded, was ice cooled to precipitate crystals. The thus-precipitatedcrystals were collected by filtration, washed with water and dried toobtain the product. (6.91 g, yield: 94.0%).

EXAMPLE 28 N-(2-chloroethyl)-α-(3-ethyl-5,6-dimethylpyrazine-2-oxy)phenyl acetamide (compound 653)

Triethylamine (3.7 ml, 26.6 mM) was added to compound 652 (7.50 g, 26.2mM) dissolved in tetrahydrofuran (44 ml) and pivaloylchloride (3.21 g,26.3 mM) was added dropwise at -5° C., then the mixture was stirred for30 minutes. Chloroform (26 ml) in solution with 2-chloroethylaminehydrochloride (3.05 g, 26.3 mM) and triethylamine (3.7 ml) was addeddropwise thereto with cooling at 0° to -5° C., then the mixture wasstirred for 1 hour with ice cooling and for 4 hours at room temperature.Chloroform was added to the reaction mixture and the mixture was washedwith dilute aqueous potassium carbonate. The aqueous layer was furtherextracted twice with chloroform. The organic layer were combined, driedwith anhydrous magnesium sulfate, and concentrated in vacuo. The residuewas charged on a column of silica gel (C-200, 170 g), and elutedsuccessively with benzene, benzene-ethyl acetate (40:1) andbenzene-ethyl acetate (10:1) to obtain the product (6.46 g, yield70.4%).

EXAMPLES 29-36 N-(2-substitutedethyl)-α-(3-ethyl-5,6-dimethylpyrazine-2-yl oxy) phenyl acetamide

A base (8.0 mM) was added to benzene (30 ml) in solution with compound653 (1.39 g, 4.0 mM) and triethylamine (1.12 ml) and the mixture wasrefluxed overnight. The reaction mixture was washed with dilute aqueouspotassium carbonate, and the aqueous layer was further extracted threetimes with chloroform. The organic layers (benzene and chloroform) werecombined, dried with anhydrous magnesium sulfate, and concentrated invacuo. The residue was charged on a column of silica gel (C-200, 65 g)and eluted successively with chloroform and chloroform-methanol (100:1)to obtain the compounds in Table 10.

Table 10 shows the identity of the base and its amount used, thecompounds and their yield in weight and percentage in each of the aboveexamples.

EXAMPLE 37 Methyl (3-benzyl-5,6-diethylpyrazine-2-yl oxy) acetate(compound 654)

A solution of 4N-CH₃ ONa/methanol (10.0 ml, 40 mM) was added to asolution of 2-hydroxy-3-benzyl-5,6-diethylpyrazine (9.68 g, 40 mM) inanhydrous methanol (120 ml), and methanol was distilled off in vacuo.The residue was dissolved in dimethylformamide (150 ml). Methylchloroacetate (4.34 g, 40 mM) was added thereto, and the mixture wasstirred at 100° C. for 5 hours. The reaction mixture was concentrated invacuo, diluted aqueous potassium carbonate was added to the residue andthe aqueous layer was extracted three times with chloroform. The extractwas dried with anhydrous magnesium sulfate, and concentrated in vacuo.The residue was charged on a column of silcia gel (C-200, 170 g) andeluted successively with benzene and benzene-ethyl acetate (100:1) toobtain the product. (11.41 g, yield: 90.8%).

EXAMPLE 38 (3-benzyl-5,6-diethylpyrazine-2-yl oxy) acetate (compound655)

Aqueous 2N-NaOH (34 ml) was added to compound 954 (10.68 g, 34.0 mM)dissolved in methanol (34 ml) and the mixture was stirred for 3 hours.2N-HCl (34 ml) was added to the reaction mixture and the precipitatedcrystals were collected by filtration, washed completely with water anddried to obtain the product. (8.86 g, yield: 86.9%).

EXAMPLE 39 N-(2-chloroethyl)-(3-benzyl-5,6-diethylpyrazine-2-yl oxy)acetamide (compound 656)

Pivaloyl chloride (3.66 g, 30 mM) was added dropwise at -5° C. tocompound 655 (8.62 g, 28.7 mM) and triethylamine (4.2 ml, 30 mM)dissolved in tetrahydrofuran (50 ml), then the mixture was stirred for30 minutes. Chloroform (30 ml) in solution with 2-fluoroethylaminehydrochloride (3.48 g) and triethylamine (4.2 ml) was added dropwisethereto with cooling at 0° to -5° C. then the mixture was stirred for 1hour with ice cooling and 4 hours at room temperature. Dilute aqueouspotassium carbonate was added to the reaction mixture and the mixturewas extracted three times with chloroform. The extract was dried withanhydrous magnesium sulfate, and concentrated in vacuo. The residue wascharged on a column of silica gel (C-200, 175 g) and eluted successivelywith benzene and benzene-ethyl acetate (5:1) to obtain the product.(9.21 g, yield: 88.8%).

EXAMPLES 40-46 N-(2-substitutedethyl)-(3-benzyl-5,6-dimethylpyrazine-2-yl oxy) acetamide

Benzene (30 ml) in solution with compound 656 (1.27 g, 3.5 mM),triethylamine (0.98 ml, 7 mM) and a base (7 mM) was refluxed. Diluteaqueous potassium carbonate was added to the reaction mixture and themixture was extracted three times with chloroform. The organic layer wasdried with anhydrous magnesium sulfate and concentrated in vacuo. Theresidue was charged on a column of silica gel (C-200, 80 g) and elutedsuccessively with chloroform and chloroform-methanol (100:1) to obtainthe compounds in Table 11.

Table 11 shows the identity of the base and its amount used, the refluxtime, and the product and yield in weight and percentage in each of theabove examples.

EXAMPLES 47-51 Methyl (3,5,6-trialkylpyrazine-2-yl oxy) acetate

Metallic sodium (1.15 g) was dissolved in anhydrous methanol (100 ml). Astarting material 2-hydroxy-3,5,6-trialkylpyrazine (50 mM) was dissolvedtherein, and methanol was distilled off in vacuo to obtain the sodiumsalt thereof. Dimethylformamide (100 ml) and methyl chloroacetate (5.43g, 50 mM) were added thereto, then the mixture was extracted three timeswith chloroform. The extract was dried with anhydrous magnesium sulfateand concentrated in vacuo. The residue was charged on a column of silicagel (C-200) and eluted successively with benzene and benzene-ethylacetate (20:1) to obtain the compounds in Table 12.

Table 12 shows the identity of the starting compound and its amountused, the reaction time, the amount of silica gel used and the productand yield in weight and percentage in each of the above examples.

EXAMPLES 52-57 2-(2-hydroxyethoxy)-3,5,6-trialkylpyrazine

A starting compound was dissolved in methanol. 6-8 equivalents of NaBH₄were added stepwise while refluxing. The reaction mixture wasconcentrated in vacuo, water was added thereto, then the mixture wasextracted three times with chloroform. The extract was dried withanhydrous magnesium sulfate and concentrated in vacuo. The residue wascharged on a column of silica gel (C-200) and eluted successively withbenzene and benzene-ethyl acetate (10:1) to obtain the compounds inTable 13.

Table 13 shows the identity of the starting compound and its amountused, the amount of NaBH₄ used, the reflux time, the amount of silicagel used and the product and yield in weight and percentage in each ofthe above examples.

EXAMPLES 58-66 2-(2-substituted ethoxy)-3,5,6-trimethylpyrazine

Thionyl chloride (0.56 ml, 1.3 equivalent) was added dropwise with icecooling to compound 679 (1.10 g, 6.0 mM) dissolved in chloroform and themixture was stirred at room temperature for 2.5 hours. Dilute aqueouspotassium carbonate was added to the reaction mixture and the mixturewas extracted three times with chloroform. The extract, which was driedwith anhydrous sodium sulfate, was concentrated in vacuo. Benzene (30ml), triethylamine (1.68 ml, 12 mM) and a base (12 mM) were added to theresidue, and the mixture was refluxed. Dilute aqueous potassiumcarbonate was added to the reaction mixture, and the mixture wasextracted three times with chloroform. The extract was dried withanhydrous magnesium sulfate and concentrated in vacuo. The residue wascharged on a column of silica gel (C-200, 75 g) and eluted successivelywith chloroform and chloroform-methanol (200:1) to obtain the compoundsin Table 14.

Table 14 shows the identity of the base and its amount used, the refluxtime, and the product and yield in weight and percentage in each of theabove examples.

EXAMPLES 67-72 2(2-substituted ethoxy)-3-isopropyl-5,6-diethylpyrazine

Thionyl chloride (0.47 ml, 1.3 equivalent) was added dropwise with icecooling to compound 683 (1.19 g, 5.0 mM) dissolved in chloroform (5 ml)and the mixture was stirred at room temperature for 4 hours. Diluteaqueous potassium carbonate was added to the reaction mixture and themixture was extracted three times with chloroform. The extract, whichwas dried with anhydrous sodium sulfate, was concentrated in vacuo.Benzene (30 ml), triethylamine (1.40 ml, 10 mM) and a base (10 mM) wereadded to the residue, and the mixture was refluxed. Dilute aqueouspotassium carbonate was added to the reaction mixture, and the mixturewas extracted three times with chloroform. The extract was dried withanhydrous magnesium sulfate and concentrated in vacuo. The residue wascharged on a column of silcia gel (C-200, 75 g) and eluted successivelywith chloroform and chloroform-methanol (200:1) to obtain the compoundsin Table 15.

Table 15 shows the identity of the base and its amount used, the refluxtime, and the product and yield in weight and percentage in each of theabove examples.

EXAMPLES 73-88 2-(2-substituted ethoxy)-3-ethyl-5,6-dimethylpyrazine

Thionyl chloride (0.43 ml, 1.3 equivalent) was added dropwise with icecooling to compound 680 (0.98 g, 5.0 mM) dissolved in chloroform (5 ml)and the mixture was stirred at room temperature for 3 hours. Diluteaqueous potassium carbonate was added to the reaction mixture and themixture was extracted three times with chloroform. The extract, whichwas dried with anhydrous sodium sulfate, was concentrated in vacuo.Benzene (60 ml), triethylamine (1.40 ml, 10 mM) and a base (10 mM) wereadded to the residue, and the mixture was refluxed. Dilute aqueouspotassium carbonate was added to the reaction mixture, and the mixturewas extracted three times with chloroform. The extract was dried withanhydrous magnesium sulfate and concentrated in vacuo. The residue wascharged on a column of silica gel (C-200, 75 g) and eluted successivelywith chloroform and chloroform-methanol to obtain the compounds in Table16.

Table 16 shows the identity of the base and its amount used, the refluxtime, the ratio of chloroform-methanol in the column chromatography, andthe product and yield in weight and percentage in each of the aboveexamples.

EXAMPLES 89-91 2-(2-substituted ethoxy)-3-benzyl-5,6-dimethylpyrazine

Thionyl chloride (0.36 ml, 1.3 equivalent) was added dropwise with icecooling to compound 681 (1.04 g, 4.0 mM) dissolved in chloroform (5 ml)and the mixture was stirred at room temperature for 3 hours. Diluteaqueous potassium carbonate was added to the reaction mixture and themixture was extracted three times with chloroform. The extract, whichwas dried with anhydrous sodium sulfate, was concentrated in vacuo.Benzene (30 ml), triethylamine (1.40 ml, 10 mM) and a base (8.0 mM) wereadded to the residue, and the mixture was refluxed. Dilute aqueouspotassium carbonate was added to the reaction mixture, and the mixturewas extracted three times with chloroform. The extract was dried withanhydrous magnesium sulfate and concentrated in vacuo. The residue wascharged on a column of silica gel (C-200, 75 g) and eluted successivelywith chloroform and chloroform-methanol to obtain the compounds in Table17.

Table 17 shows the identity of the base and its amount used, the refluxtime, ratio of chloroform-methanol in column chromatography, and theproduct and yield in weight and percentage in each of the aboveexamples.

EXAMPLES 92-98 2-(2-substituted ethoxy)-3-isopropyl-5,6-dimethylpyrazine

Thionyl chloride (0.47 ml, 1.3 equivalent) was added dropwise with icecooling to compound 682 (1.05 g, 4.0 mM) dissolved in chloroform (5 ml)and the mixture was stirred at room temperature for 3.5 hours. Diluteaqueous potassium carbonate was added to the reaction mixture and themixture was extracted three times with chloroform. The extract, whichwas dried with anhydrous sodium sulfate, was concentrated in vacuo.Benzene (30 ml), triethylamine (1.40 ml, 10 mM) and a base (10 mM) wereadded to the residue, and the mixture was refluxed. Dilute aqueouspotassium carbonate was added to the reaction mixture, and the mixturewas extracted three times with chloroform. The extract was dried withanhydrous magnesium sulfate and concentrated in vacuo. The residue wascharged on a column of silica gel (C-200, 75 g) and eluted successivelywith chloroform and chloroform-methanol to obtain the compounds in Table18.

Table 18 shows the identity of the base and its amount used, the refluxtime, the ratio of chloroform-methanol in the column chromatography, andthe product and yield in weight and percentage in each of the aboveexamples.

EXAMPLES 99-100 2-(2-substituted ethoxy)-3-isobutyl-5,6-diethylpyrazine

Thionyl chloride (0.47 ml, 1.3 equivalent) was added dropwise with icecooling to compound 684 (1.26 g, 5.0 mM) dissolved in chloroform (5 ml)and the mixture was stirred at room temperature for 4 hours. Diluteaqueous potassium carbonate was added to the reaction mixture and themixture was extracted three times with chloroform. The extract, whichwas dried with anhydrous sodium sulfate, was concentrated in vacuo.Benzene (30 ml), triethylamine (1.40 ml, 10 mM) and a base (10 mM) wereadded to the residue, and the mixture was refluxed. Dilute aqueouspotassium carbonate was added to the reaction mixture, and the mixturewas extracted three times with chloroform. The extract was dried withanhydrous magnesium sulfate and concentrated in vacuo. The residue wascharged on a column of silica gel (C-200, 75 g) and eluted successivelywith chloroform and chloroform-methanol to obtain the compounds in Table19.

Table 19 shows the identity of the base and its amount used, the refluxtime, and the product and yield in weight and percentage in each of theabove examples.

COMPARATIVE EXAMPLE 1 2-hydroxy-3-benzyl-5,6,7,8-tetrahydroquinoxaline

A methanol (30 ml) solution of cyclohexane-1,2-dione (13.44 g, 0.12M)was added to phenylalanineamide hydrochloride (20.05 g, 0.1M) dissolvedin methanol (200 ml) with cooling below -30° C., and aqueous 12.5N-NaOH(20 ml) was added dropwise thereto. The reaction mixture was stirred atbelow -30° C. for 30 minutes and was further stirred at room temperaturefor 3 hours. Conc. hydrochloric acid (25 ml) was added to the reactionmixture, and sodium bicarbonate (15 g) was added after 10 minutesstirring, the solvent then being distilled off in vacuo. The residue, towhich was added water, was extracted three times with chloroform, andthe extract was dried with anhydrous magnesium sulfate and concentratedin vacuo. The residue was recrystallized from acetone to obtain theproduct. (19.7 g, yield: 82.1%).

COMPARATIVE EXAMPLE 22-hydroxy-3-(2-phenylethyl)-5,6,7,8-tetrahydroquinoxaline

A methanol (20 ml) solution of cyclohexane-1,2-dione (5.38 g) was addedto α-amino-2-phenylacetic acidamide hydrochloride (8.58 g, 40 mM)dissolved in methanol (100 ml) with cooling below -30° C., and aqueous12.5N-NaOH was added dropwise thereto. The reaction mixture was stirredat below -30° C. for 30 minutes, and the mixture was stirred at roomtemperature for 6 hours. Conc. hydrochloric acid (8 ml) was added to thereaction mixture, and sodium bicarbonate (6.0 g) was added after 10minutes stirring, the solvent then being distilled off in vacuo. Theresidue, to which was added water, was extracted three times withchloroform, dried with anhydrous magnesium sulfate and concentrated invacuo. The residue was recrystallized from acetone to obtain theproduct. (6.79 g, yield: 66.8%).

COMPARATIVE EXAMPLE 3 2-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoxaline

A methanol (20 ml) solution of cyclohexane-1,2-dione (6.72 g) was addedto alanine (4.4 g, 50 mM) dissolved in methanol (100 ml) with coolingbelow -30° C., and aqueous 12.5N-NaOH (5 ml) was added dropwise thereto.The reaction mixture was stirred at below -30° C. for 30 minutes, andthe mixture was stirred at room temperature for 3 hours. Conc.hydrochloric acid (8 ml) was added to the reaction mixture, and sodiumbicarbonate (5 g) was added after 10 minutes stirring, the solvent thenbeing distilled off in vacuo. The residue, to which was added water, wasextracted three times with chloroform, dried with anhydrous magnesiumsulfate and concentrated in vacuo. The residue was recrystallized fromacetone to obtain the product as pale yellowish crystals. (6.50 g,yield: 79.0%).

COMPARATIVE EXAMPLE 4 2-hydroxy-3-ethyl-5,6,7,8-tetrahydroquinoxaline

A methanol (20 ml) solution of cyclohexane-1,2-dione (6.72 g, 60 mM) wasadded to a methanol solution (100 ml) of α-aminobutylamide (5.1 g, 50mM) with cooling below -30° C., and aqueous 12.5N-NaOH (5 ml) was addeddropwise thereto. The reaction mixture was stirred at below -30° C. for30 mins. and the mixture was stirred at room temperature for 3 hours.Conc. hydrochloric acid (6.25 ml) was added to the reaction mixture andsodium bicarbonate (5 g) was added after 10 minutes stirring, thesolvent being distilled off in vacuo. The residue, to which was addedwater, was extracted three times with chloroform, dried with anhydrousmagnesium sulfate and concentrated in vacuo. The residue wasrecrystallized from acetone to obtain the colorless crystals. (5.30 gm,yield: 60.0%).

COMPARATIVE EXAMPLES 5-182-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline

Cyclohexane-1,2-dione (6.72 g, 60 mM) was added all at once to aminoacidamine hydrochloride (50 mM) dissolved in methanol (100 ml) withcooling below -30° C., and aqueous 12N-NaOH (5 ml) was added dropwisethereto. The reaction mixture was stirred for 30 minutes with coolingbelow -30° C., and the mixture was stirred at room temperature for 5hours. Conc. hydrochloric acid (12.5 ml) was added to the reactionmixture and sodium bicarbonate (7.5 g) was added after 10 minutes,whereafter the solvent was distilled off in vacuo. The residue, to whichwas added water, was extracted three times with chloroform, dried withanhydrous sodium sulfate and concentrated in vacuo. The residue wasrecrystallized from acetone to obtain the products shown in Table 20.

Table 20 shows the identity of the acid amide hydrochloride and itsamount used and the product and yield in weight and percentage in eachof the above comparative examples.

EXAMPLE 101 Methyl (3-benzyl-5,6,7,8-tetrahydroquinoxaline-2-yl oxy)acetate (compound 656)

2-hydroxy-3-benzyl-5,6,7,8-tetrahydroquinoxaline (12.0 g, 50 mM) wasdissolved in a solution of metallic sodium (1.15 g, 50 mM) in anhydrousmethanol (200 ml), whereafter methanol was distilled off in vacuo toobtain the sodium salt thereof, which was suspended in dimethylformamide(100 ml). Methyl chloroacetate (5.43 g, 50 mM) was added thereto and themixture was stirred at 100° C. for 3 hours. The reaction mixture wasconcentrated in vacuo. Dilute aqueous sodium carbonate was added to theresidue, which was then extracted three times with chloroform, and theextract was dried with anhydrous sodium sulfate and concentrated invacuo. The residue was charge on a column of silica gel (C-200, 180 g)and eluted successively with benzene and benzene-ethyl acetate (10:1) toobtain the product. (14.12 g, yield: 90.5%).

EXAMPLE 102 (3-benzyl-5,6,7,8-tetrahydroquinoxaline-2-yl oxy) acetate(compound 660)

Aqueous 2N-NaOH (30 ml) was added to compound 656 (9.42 g, 30.2 mM)dissolved in methanol (30 ml) and the mixture was stirred for 3 hours atroom temperature. 2N-HCl (30 ml) was added to the reaction mixture withice cooling and the precipitated crystals were collected by filtration,washed with water and dried to obtain most of the product. (8.10 g) Thefiltrate was concentrated in vacuo and the residue was extracted withhot ethanol, then the extract was concentrated in vacuo. The residuedissolved in dilute aqueous NaOH, was neutralized with 1N-HCl and theprecipitated crystals were collected by filtration, washed with water,then dried to obtain the remainder of the product. (0.32 g) (Total: 8.42g, yield: 93.6%).

EXAMPLE 103N-(2-chloroethyl)-(3-benzyl-5,6,7,8-tetrahydroquinoxaline-2-yl oxy)acetamide (compound 661)

Pivaloyl chloride (3.05 g, 25 mM) was added dropwise at -5° C. tocompound 660 (7.45 g, 25 mM) and triethylamine (3.5 ml, 25 mM) dissolvedin tetrahydrofuran (45 ml), then the mixture was stirred for 30 minutes.Chloroform (25 ml) in solution with 2-chloroethylamine hydrochloride(2.90 g) and triethylamine (3.5 ml) was added dropwise thereto, then themixture was stirred for 1 hour with ice cooling and 4 hours at roomtemperature. Dilute aqueous potassium carbonate was added to thereaction mixture and the mixture was extracted twice with chloroform.The extract was dried with anhydrous sodium sulfate, and concentrated invacuo. The residue was charged on a column of silica gel (C-200, 175 g)and eluted successively with benzene and benzene-ethyl acetate to obtainthe product. (7.142 g, yield: 79.5%).

EXAMPLES 104-109 N-(2-substitutedethyl)-(3-benzyl-5,6,7,8-tetrahydroquinoxaline-2-yl oxy) acetamide

Benzene (30 ml) in solution with compound 661 (1.08 g, 3.0 mM),triethylamine (0.84 m) and a base (6.0 mM) was refluxed. Dilute aqueouspotassium carbonate was added to the reaction mixture, and the aqueouslayer was extracted three times with chloroform. The organic layer wasdried with anhydrous sodium sulfate, and concentrated in vacuo. Theresidue was charged on a column of silica gel (C-200, 80 g) and elutedsuccessively with benzene and benzene-ethyl acetate (10:1) to obtain thecompounds in Table 21.

Table 21 shows the identity of the base and its amount used, the refluxtime, the products and the yield in weight and percentage, in each ofthe above examples.

EXAMPLES 110-121 Methyl (3-alkyl-5,6,7,8-tetrahydroquinoxaline-2-yl oxy)acetate

Metallic sodium (1.15 g) was dissolved in anhydrous methanol (100 ml).2-hydroxy-3,-alkyl-5,6,7,8-tetrahydroquinoxaline (50 mM) was dissolvedtherein, and methanol was distilled off in vacuo to obtain the sodiumsalt. Dimethylformamide (100 ml) and methyl chloroacetate (5.43 g, 50mM) were added thereto and the mixture was stirred at 100° C. Thereaction mixture was concentrated in vacuo, and dilute aqueous sodiumcarbonate was added to the residue, which was then extracted three timeswith chloroform, and the extract was dried with anhydrous sodium sulfateand concentrated in vacuo. The residue was charged on a column of silicagel (C-200) and eluted successively with benzene and benzene-ethylacetate (20:1) to obtain the compounds in Table 22.

Table 22 shows the identity of the starting compound and its amountused, the reaction time, the amount of silica gel used, the products andthe yield in weight and percentage in each of the above examples.

EXAMPLES 122-1332-(2-hydroxyethoxy)-3-alkyl-5,6,7,8-tetrahydroquinoxaline

The starting compound was dissolved in methanol. 6-8 equivalents ofNaBH₄ were added several portionwise while refluxing. The reactionmixture was concentrated in vacuo, water was added thereto, then themixture was extracted three times with chloroform. The extract was driedwith anhydrous sodium sulfate and concentrated in vacuo. The residue wascharged on a column of silica gel (C-200) and eluted successively withbenzene and benzene-ethyl acetate (10:1) to obtain the compounds inTable 23.

Table 23 shows the identity of the starting compound and its amountused, the amount of methanol used, the amount of NaBH₄ used, the refluxtime, the amount of silica gel used and the product and yield in weightand percentage in each of the above examples.

EXAMPLES 134-185 2-(2-substitutedethoxy)-3-alkyl-5,6,7,8-tetrahydroquinoxaline

Thionyl chloride (1.3 equivalent) was added dropwise with ice cooling toa starting compound2-(2-hydroxyethoxy)-3-alkyl-5,6,7,8-tetrahydroquinoxaline (3-5 mM)dissolved in chloroform and the mixture was stirred at room temperaturefor 2.5 hours to chlorinate the compound. The reaction mixture waspoured into dilute aqueous potassium carbonate and extracted three timeswith chloroform. The extract, which was dried with anhydrous sodiumsulfate, was concentrated in vacuo. Benzene (30 ml), triethylamine (2equivalents) and a base (2 equivalents) were added to the residue, andthe mixture was refluxed. The reaction mixture was poured into diluteaqueous potassium carbonate, and the mixture was extracted three timeswith chloroform. The extract was dried with anhydrous sodium sulfate andconcentrated in vacuo. The residue was charged on a column of silica gel(C-200, 75 g) and eluted successively with chloroform andchloroform-methanol (200:1) to obtain the compounds in Table 24.

Table 24 shows the identity of the starting compound and its amountused, the chlorination reaction time, the base and its amount used, thereflux time, and the product and yield in weight and percentage in eachof the above examples.

                                      TABLE 7                                     __________________________________________________________________________    2-(substituted carbonylmethoxy)-3,5,6-trimethylpyrazine                       Base                          Yield                                                                             Yield                                       Example                                                                            name           used (g)                                                                           Product                                                                            (g) (%)                                         __________________________________________________________________________          ##STR180##    0.50 066  1.12                                                                              80.5                                        8                                                                                   ##STR181##    0.43 067  1.10                                                                              83.6                                        9                                                                                   ##STR182##    0.66 068  1.23                                                                              79.8                                        10   H.sub.2 NCH.sub.2 CH.sub.2OH                                                                 0.32 069  0.88                                                                              73.6                                        11                                                                                  ##STR183##    0.43 070  0.91                                                                              82.0                                        12                                                                                  ##STR184##    0.44 075  1.10                                                                              83.0                                        __________________________________________________________________________     Product is shown by No. of compound                                      

                                      TABLE 8                                     __________________________________________________________________________    N(2-substituted ethyl)-(3,5,6-trimethylpyrazine-2-yloxy)acetamide                                              solvent                                      Base                        reaction                                                                           ratio    Yield                                                                             Yield                           Example                                                                            name            used (g)                                                                             (time)                                                                             (hr.)                                                                             product                                                                            (g) (%)                             __________________________________________________________________________    15   40% HN(CH.sub.3).sub.2 aqueous solution                                                       8.68   1    50:1                                                                              071  0.22                                                                              27.6                            16                                                                                  ##STR185##     0.53 (6 mM)                                                                          1.5  100:1                                                                             073  0.41                                                                              44.4                            17                                                                                  ##STR186##     0.43 (5 mM)                                                                          1    20:1                                                                              074  0.55                                                                              59.9                            18                                                                                  ##STR187##     0.78 (6 mM)                                                                          1.5  50:1                                                                              076  0.58                                                                              55.0                            19                                                                                  ##STR188##     3.44 (40 mM)                                                                         1.5  10:1                                                                              103  0.94                                                                              30.0                            20                                                                                  ##STR189##     0.60 (6 mM)                                                                          1    50:1                                                                              105  0.27                                                                              28.0                            21   H.sub.2 N C.sub.6 H.sub.11                                                                    0.60 (6 mM)                                                                          1.5  50:1                                                                              650  0.17                                                                              17.7                            __________________________________________________________________________     product is shown by No. of compound                                      

                                      TABLE 9                                     __________________________________________________________________________    N(2-substituted ethyl)-(3,5,6-trimethylpyrazine-2-yloxy)acetamide                                         reaction                                          BASE                        time solvent  Yield                                                                             Yield                           Example                                                                            name            used (g)                                                                             (hr.)                                                                              ratio                                                                             Product                                                                            (g) (%)                             __________________________________________________________________________    23                                                                                  ##STR190##     1.68 (8 mM)                                                                          8    100:1                                                                             135  0.50                                                                              30.5                            24                                                                                  ##STR191##     1.41 (8 mM)                                                                          6     50:1                                                                             136  0.43                                                                              27.1                            25                                                                                  ##STR192##     1.68 (8 mM)                                                                          8    100:1                                                                             137  0.50                                                                              30.5                            __________________________________________________________________________     product is shown by No. of compound                                      

                                      TABLE 10                                    __________________________________________________________________________    N(2-substituted ethyl)-α-(3-ethyl-5,6-dimethylpyrazine-2-yloxy)-phen    ylacetamide                                                                   BASE                            Yield                                                                             Yield                                     Example                                                                            name             used (g)                                                                           product                                                                            (g) (%)                                       __________________________________________________________________________    29                                                                                  ##STR193##      0.70 341  0.94                                                                              59.0                                      30                                                                                  ##STR194##      1.41 342  1.48                                                                              76.0                                      31                                                                                  ##STR195##      1.69 343  1.27                                                                              60.9                                      32                                                                                  ##STR196##      1.77 344  1.32                                                                              62.0                                      33                                                                                  ##STR197##      1.96 345  0.91                                                                              41.0                                      34                                                                                  ##STR198##      1.30 346  1.20                                                                              63.4                                      35                                                                                  ##STR199##      1.67 347  1.28                                                                              61.5                                      36                                                                                  ##STR200##      1.80 348  1.77                                                                              82.6                                      __________________________________________________________________________     product is shown by No. of compound                                      

                                      TABLE 11                                    __________________________________________________________________________    N(2-substituted ethyl)-(3-benzyl-5,6-dimethylpyrazine-2-yloxy)-acetamide      BASE                      reaction  Yield                                                                             Yield                                 Example                                                                            name            used (g)                                                                           (day)                                                                              product                                                                            (g) (%)                                   __________________________________________________________________________    40                                                                                  ##STR201##     1.24 2    376  1.54                                                                              87.8                                  41                                                                                  ##STR202##     1.48 2    377  1.48                                                                              81.5                                  42                                                                                  ##STR203##     1.48 2    379  1.17                                                                              62.4                                  43                                                                                  ##STR204##     1.38 1    381  1.29                                                                              70.7                                  44                                                                                  ##STR205##     1.58 2    382  1.38                                                                              71.8                                  45                                                                                  ##STR206##     0.61 2    657  0.73                                                                              50.6                                  46                                                                                  ##STR207##     1.14 1    658  1.15                                                                              67.6                                  __________________________________________________________________________     product is shown by No. of compound                                      

                                      TABLE 12                                    __________________________________________________________________________    methyl (3,5,6-trialkylpyrazine-2-yloxy)-acetate                               starting material                                                             R.sub.3 N OH       reaction                                                   R.sub.2 N R.sub.1                                                                             used                                                                             time silica-gel                                                                              Yield                                                                             Yield                                   Example                                                                            R.sub.1                                                                            R.sub.2                                                                          R.sub.3                                                                          (g)                                                                              (hr.)                                                                              (g)  product                                                                            (g) (%)                                     __________________________________________________________________________    47   Et   Me Me 7.60                                                                             2.5  160  662  9.62                                                                              85.9                                    48   --CH.sub.2 Ph                                                                      Me Me 10.70                                                                            2.5  210  663  12.03                                                                             84.1                                    49   iso-Pro                                                                            Me Me 8.3                                                                              2.5  160  664  9.92                                                                              83.4                                    50   "    Et Et 9.70                                                                             2.5  180  665  12.77                                                                             96.0                                    51   iso-Bu                                                                             Et Et 10.40                                                                            3    230  666  12.86                                                                             91.9                                    __________________________________________________________________________     product is shown by No. of compound                                      

                                      TABLE 13                                    __________________________________________________________________________    2-(2-hydroxyethoxy)-3,5,6-trialkylpyrazine                                                            reaction                                              starting material                                                                            methanol                                                                           NaBH.sub.4                                                                        time silica-gel                                                                             Yield                                                                             Yield                               Example                                                                            name                                                                             used g (mM)                                                                          (ml) (g) (hr.)                                                                              (g)  product                                                                           (g) (%)                                 __________________________________________________________________________    52   034                                                                              17.00 (80.95)                                                                        200  18.6                                                                              3.0  200  679 12.84                                                                             87.2                                53   662                                                                               9.62 (42.94)                                                                        200  9.9 4.0  120  680 7.69                                                                              91.3                                54   663                                                                               8.75 (30.6)                                                                         150  9.4 2.5  160  681 7.22                                                                              91.5                                55   664                                                                              19.67 (82.65)                                                                        200  25.2                                                                              3.0  200  682 15.51                                                                             89.4                                56   665                                                                               9.18 (34.5)                                                                         150  10.5                                                                              4.0  200  683 7.48                                                                              91.1                                57   666                                                                               7.32 (26.14)                                                                        100  8.0 3.5  160  684 5.94                                                                              90.1                                __________________________________________________________________________     product is shown by No. of compound                                      

                                      TABLE 14                                    __________________________________________________________________________    2-(2-substituted ethoxy)-3,5,6-trimethylpyrazine                                                        reaction                                            BASE                      time      Yield                                                                             Yield                                 Example                                                                            name            used (g)                                                                           (hr.)                                                                              product                                                                            (g) (%)                                   __________________________________________________________________________    58                                                                                  ##STR208##     1.05 2.5  536  0.95                                                                              63.1                                  59                                                                                  ##STR209##     1.10 2.5  537  1.03                                                                              68.9                                  60                                                                                  ##STR210##     2.02 3.0  538  1.31                                                                              64.2                                  61                                                                                  ##STR211##     2.11 2.5  539  1.62                                                                              72.1                                  62                                                                                  ##STR212##     1.94 2.0  540  1.59                                                                              74.0                                  63                                                                                  ##STR213##     2.25 2.5  541  1.56                                                                              66.9                                  64                                                                                  ##STR214##     1.70 5.0  810  1.28                                                                              70.0                                  65                                                                                  ##STR215##     3.90 5.0  822  1.56                                                                              94.5                                  66   HNEt.sub.2      0.88 5.0  842  0.51                                                                              35.7                                  __________________________________________________________________________     product is shown by No. of compound                                      

                                      TABLE 15                                    __________________________________________________________________________    2-(2-substituted ethoxy)-3-isopropyl-5,6-diethylpyrazine                                                reaction                                            BASE                      time      Yield                                                                             Yield                                 Example                                                                            name            used (g)                                                                           (hr.)                                                                              product                                                                            (g) (%)                                   __________________________________________________________________________    67                                                                                  ##STR216##     0.85 3.0  550  0.83                                                                              54.4                                  68                                                                                  ##STR217##     1.42 2.5  551  0.93                                                                              51.4                                  69                                                                                  ##STR218##     1.76 3.0  552  1.05                                                                              52.8                                  70                                                                                  ##STR219##     2.20 3.0  553  1.01                                                                              46.0                                  71                                                                                  ##STR220##     1.30 5.0  826  1.15                                                                              66.2                                  72   HNEt.sub.2      0.73 6.5  848  0.36                                                                              25.2                                  __________________________________________________________________________     product is shown by No. of compound                                      

                                      TABLE 16                                    __________________________________________________________________________    2-(2-substituted ethoxy)-3-ethyl-5,6-dimethylpyrazine                                                         reaction                                      BASE                            time solvent  Yield                                                                             Yield                       Example                                                                            name                  used (g)                                                                           (hr.)                                                                              ratio                                                                             product                                                                            (g) (%)                         __________________________________________________________________________    73                                                                                  ##STR221##           0.87 2.5  200:1                                                                             491  0.66                                                                              49.8                        74                                                                                  ##STR222##           0.85 2.0  200:1                                                                             492  0.79                                                                              60.1                        75                                                                                  ##STR223##           1.00 2.0  200:1                                                                             493  0.67                                                                              48.4                        76                                                                                  ##STR224##           1.00 2.0   30:1                                                                             494  0.84                                                                              44.6                        77                                                                                  ##STR225##           1.20 2.0  100:1→  10:1                                                               495  0.73                                                                              47.4                        78                                                                                  ##STR226##           1.74 2.0  50:1                                                                              496  1.13                                                                              64.2                        79                                                                                  ##STR227##           1.68 2.0  200:1                                                                             497  1.15                                                                              65.0                        80                                                                                  ##STR228##           2.11 2.0  200:1                                                                             498  1.10                                                                              56.6                        81                                                                                  ##STR229##           2.06 2.0  200:1                                                                             499  1.17                                                                              60.9                        82                                                                                  ##STR230##           1.94 2.0  200:1                                                                             500  1.17                                                                              62.9                        83                                                                                  ##STR231##           2.21 2.0  200:1                                                                             501  1.40                                                                              70.2                        84                                                                                  ##STR232##           2.35 2.0  200:1                                                                             502  0.62                                                                              30.0                        85                                                                                  ##STR233##           2.08 2.0  200:1                                                                             503  1.00                                                                              51.8                        86                                                                                  ##STR234##           2.25 2.0  200:1                                                                             504  1.14                                                                              56.6                        87                                                                                  ##STR235##           1.42 2.0  200:1                                                                             812  0.67                                                                              42.0                        88   HNEt.sub.2            0.73 3.0  200:1                                                                             844  0.23                                                                              18.8                        __________________________________________________________________________     product is shown by No. of compound                                      

                                      TABLE 17                                    __________________________________________________________________________    2-(2-substituted ethoxy)-3-benzyl-5,6-dimethylpyrazine                                                  reaction                                            BASE                      time solvent  Yield                                                                             Yield                             Example                                                                            name            used (g)                                                                           (hr.)                                                                              ratio                                                                             product                                                                            (g) (%)                               __________________________________________________________________________    89                                                                                  ##STR236##     0.70 2.0  200:1                                                                             511  0.57                                                                              43.6                              90                                                                                  ##STR237##     1.04 2.0  200:1                                                                             512  1.04                                                                              62.5                              91                                                                                  ##STR238##     1.80 2.0  200:1                                                                             516  1.20                                                                              64.6                              __________________________________________________________________________     product is shown by No. of compound                                      

                                      TABLE 18                                    __________________________________________________________________________    2-(2-substituted ethoxy)-3-isopropyl-5,6-dimethylpyrazine                                               reaction                                            BASE                      time solvent  Yield                                                                             Yield                             Example                                                                            name            used (g)                                                                           (hr.)                                                                              ratio                                                                             product                                                                            (g) (%)                               __________________________________________________________________________    92                                                                                  ##STR239##     0.87 2.5  200:1                                                                             544  0.89                                                                              63.8                              93                                                                                  ##STR240##     2.11 2.5  200:1                                                                             546  1.57                                                                              80.8                              94                                                                                  ##STR241##     2.25 2.5  200:1                                                                             547  1.42                                                                              68.2                              95                                                                                  ##STR242##     1.43 3.0  200:1                                                                             697  0.94                                                                              56.3                              96                                                                                  ##STR243##     1.43 2.0  200:1                                                                             814  0.77                                                                              46.0                              97                                                                                  ##STR244##     1.30 2.5  200:1                                                                             825  1.24                                                                              77.0                              98                                                                                  ##STR245##     0.85 5.0  200:1                                                                             834  1.17                                                                              68.3                              99   HNEt.sub.2      0.73 18.0 200:1                                                                             846  0.12                                                                              11.2                              __________________________________________________________________________     product is shown by No. of compound                                      

                                      TABLE 19                                    __________________________________________________________________________    2-(2-substituted ethoxy)-3-isobutyl-5,6-diethylpyrazine                                                  reaction                                           BASE                       time      Yield                                                                             Yield                                Example                                                                            name             used (g)                                                                           (hr.)                                                                              product                                                                            (g) (%)                                  __________________________________________________________________________     99                                                                                 ##STR246##      1.76 3.5  556  0.45                                                                              21.9                                 100                                                                                 ##STR247##      2.20 4.0  558  0.77                                                                              33.9                                 __________________________________________________________________________     product is shown by No. of compound                                      

                                      TABLE 20                                    __________________________________________________________________________    2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline                                ##STR248##                                                                   Reference                                                                           amino acidamide HCl                                                                       Product                                                     example                                                                             used (g)    R.sub.1  Yield (g)                                                                           Yield (%)                                    __________________________________________________________________________    5     7.63        Pro      4.75  50.0                                         6     7.63        iso-Pro  4.95  51.6                                         7     8.32        Bu       7.49  73.0                                         8     8.32        iso-Bu   6.58  64.0                                         9     8.32        sec-Bu   6.58  64.0                                         10    9.04        (CH.sub.2).sub.4 CH.sub.3                                                              9.03  82.0                                         11    9.74        (CH.sub.2).sub.5 CH.sub.3                                                              7.81  66.7                                         12    10.44       (CH.sub.2).sub.6 CH.sub.3                                                              9.33  75.0                                         13    11.14       (CH.sub.2).sub.7 CH.sub.3                                                              11.67 89.1                                         14    11.83       (CH.sub.2).sub.8 CH.sub.3                                                              10.50 72.4                                         15    12.55       (CH.sub.2).sub.9 CH.sub.3                                                              12.73 92.2                                         16    13.95       (CH.sub.2).sub.11 CH.sub.3                                                             14.00 88.1                                         17    15.35       (CH.sub.2).sub.13 CH.sub.3                                                             16.58 95.8                                         18    16.75       (CH.sub.2).sub.15 CH.sub.3                                                             18.55 99.2                                         __________________________________________________________________________

                                      TABLE 21                                    __________________________________________________________________________    N(2-substituted ethyl)-(3-benzyl-5,6,7,8-tetrahydroquinoxaline-2-yloxy)-ac    etamide                                                                                                  reaction                                           BASE                       time Product                                       Example                                                                            name             used (g)                                                                           (day)                                                                              No. of comp                                                                          Yield (g)                                                                          Yield (%)                         __________________________________________________________________________    104                                                                                 ##STR249##      1.06 1    368    1.00 66.8                              105                                                                                 ##STR250##      1.24 4    369    1.38 87.0                              106                                                                                 ##STR251##      1.27 2    370    1.07 67.0                              107                                                                                 ##STR252##      1.18 3    371    1.36 87.3                              108                                                                                 ##STR253##      1.25 3    372    1.21 76.0                              109                                                                                 ##STR254##      0.73 2    373    0.73 50.2                              __________________________________________________________________________

                                      TABLE 22                                    __________________________________________________________________________    methyl(3-alkyl-5,6,7,8-tetrahydroquinoxaline-2-yloxy)-acetate                 starting compound                                                              NOH            reaction  Product                                                   NR.sub.1                                                                             used                                                                             time silica-gel                                                                         No. of                                                                              Yield                                                                             Yield                                     Example                                                                            R.sub.1 (g)                                                                              (hr.)                                                                              (g)  compound                                                                            (g) (%)                                       __________________________________________________________________________    110  Bu      10.30                                                                            3    210  667   11.54                                                                             83.2                                      111  --(CH.sub.2).sub.4 CH.sub.3                                                           10.10                                                                            3    210  668   11.64                                                                             79.7                                      112  --(CH.sub.2).sub.5 CH.sub.3                                                           11.70                                                                            2.5  210  669   12.24                                                                             80.0                                      113  --(CH.sub.2).sub.6 CH.sub.3                                                           12.40                                                                            2.5  210  670   13.35                                                                             83.5                                      114  --(CH.sub.2).sub.7 CH.sub.3                                                           13.10                                                                            3    200  671   13.02                                                                             78.0                                      115  --(CH.sub.2).sub.8 CH.sub.3                                                           13.80                                                                            3    240  672   13.71                                                                             78.8                                      116  --(CH.sub.2).sub.9 CH.sub.3                                                           14.50                                                                            2.5  210  673   13.61                                                                             75.2                                      117  --(CH.sub.2).sub.11 CH.sub.3                                                          15.90                                                                            3    280  674   16.00                                                                             82.1                                      118  --(CH.sub.2).sub.13 CH.sub.3                                                          17.30                                                                            3    280  675   16.33                                                                             78.1                                      119  --(CH.sub.2).sub.15 CH.sub.3                                                          18.70                                                                            2.5  340  676   18.74                                                                             84.0                                      120  Pro     9.60                                                                             3    220  677   10.29                                                                             78.0                                      121  sec-Bu  10.30                                                                            2.5  260  678   11.73                                                                             84.4                                      __________________________________________________________________________

                                      TABLE 23                                    __________________________________________________________________________    2-(2-hydroxyethoxy)-3-alkyl-5,6,7,8-tetrahydroquinoxaline                                                 reaction                                          starting compound  methanol                                                                           NaBH.sub.4                                                                        time silica-gel                                                                         Product                                 Example                                                                            No. of comp                                                                          used g (mM)                                                                          (ml) (g) (hr.)                                                                              (g)  No. of comp                                                                          Yield (g)                                                                          Yield                       __________________________________________________________________________                                                      (%)                         122  667    12.40 (44.6)                                                                         200  10.2                                                                              2.5  200  685    10.63                                                                              95.3                        123  668    9.07 (31.1)                                                                          200  7.2 3.0  200  686    7.12 86.7                        124  669    9.55 (31.2)                                                                          200  9.6 2.5  200  687    7.95 91.7                        125  670    9.70 (30.3)                                                                          200  9.3 3.0  200  688    8.05 91.0                        126  671    11.10 (33.2)                                                                         300  7.8 3.0  250  689    9.31 91.6                        127  672    9.50 (27.3)                                                                          250  9.4 3.0  250  690    8.20 93.9                        128  673    10.80 (29.8)                                                                         250  9.1 2.5  250  691    9.15 92.0                        129  674    9.54 (24.46)                                                                         250  7.5 3.0  200  692    7.94 89.7                        130  675    9.56 (22.9)                                                                          250  6.9 3.0  200  693    8.63 96.6                        131  676    9.17 (32.9)                                                                          250  6.2 3.0  200  694    7.27 84.6                        132  677    7.78 (29.47)                                                                         200  9.0 3.0  200  695    6.60 95.0                        133  678    7.50 (27.0)                                                                          200  8.4 2.5  170  696    5.77 85.5                        __________________________________________________________________________

                                      TABLE 24                                    __________________________________________________________________________    2-(2-substituted ethoxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline                                 chlorin-                       reflux                                                                            product                    Exam-                                                                             starting compound                                                                         ation  BASE                    time                                                                              No. of                                                                            Yield                                                                             Yield              ple No. of comp                                                                          used g                                                                             time(hr)                                                                             name             used g (hr.)                                                                             comp                                                                              (g) (%)                __________________________________________________________________________    134 685    1.25 (5 mM)                                                                        3.0                                                                                   ##STR255##      0.87 (10 mM)                                                                         2.0 517 1.38                                                                              86.5               135 685    1.00 (4 mM)                                                                        3.0                                                                                   ##STR256##      1.42 (8 mM)                                                                          2.0 518 1.23                                                                              75.4               136 685    1.00 (4 mM)                                                                        3.0                                                                                   ##STR257##      1.69 (8 mM)                                                                          2.0 519 0.89                                                                              50.3               137 685    1.00 (4 mM)                                                                        3.0                                                                                   ##STR258##      1.80 (8 mM)                                                                          2.5 520 1.00                                                                              54.8               138 686    1.32 (5 mM)                                                                        3.5                                                                                   ##STR259##      0.87 (10 mM)                                                                         3.0 559 0.92                                                                              55.3               139 686    1.32 (5 mM)                                                                        3.5                                                                                   ##STR260##      1.42 (10 mM)                                                                         2.5 560 1.01                                                                              52.1               140 686    1.32 (5 mM)                                                                        3.5                                                                                   ##STR261##      1.76 (10 mM)                                                                         3.0 561 1.27                                                                              60.2               141 686    1.32 (5 mM)                                                                        3.5                                                                                   ##STR262##      2.08 (10 mM)                                                                         2.5 562 1.24                                                                              54.6               142 687    1.39 (5 mM)                                                                        3.5                                                                                   ##STR263##      0.87 (10 mM)                                                                         3.0 564 0.99                                                                              57.1               143 687    1.39 (5 mM)                                                                        3.5                                                                                   ##STR264##      1.42 (10 mM)                                                                         3.0 565 1.11                                                                              55.2               144 687    1.39 (5 mM)                                                                        3.5                                                                                   ##STR265##      1.76 (10 mM)                                                                         2.5 567 1.25                                                                              57.3               145 687    1.39 (5 mM)                                                                        3.5                                                                                   ##STR266##      2.10 (10 mM)                                                                         2.5 568 1.62                                                                              68.9               146 687    1.39 (5 mM)                                                                        3.5                                                                                   ##STR267##      2.08 (10 mM)                                                                         2.5 569 1.29                                                                              55.4               147 688    1.17 (4 mM)                                                                        3.0                                                                                   ##STR268##      1.14 (8 mM)                                                                          2.5 571 1.01                                                                              60.7               148 689    1.53 (5 mM)                                                                        3.0                                                                                   ##STR269##      0.87 (10 mM)                                                                         2.0 572 1.06                                                                              56.5               149 689    1.23 (4 mM)                                                                        3.0                                                                                   ##STR270##      1.14 (8 mM)                                                                          2.0 573 0.87                                                                              50.6               150 689    1.23 (4 mM)                                                                        3.0                                                                                   ##STR271##      1.42 (8 mM)                                                                          2.0 574 0.95                                                                              52.9               151 689    1.23 (4 mM)                                                                        3.0                                                                                   ##STR272##      1.68 (8 mM)                                                                          2.0 575 0.65                                                                              32.6               152 689    1.23 (4 mM)                                                                        3.0                                                                                   ##STR273##      1.67 (8 mM)                                                                          2.5 576 0.57                                                                              28.7               153 690    1.60 (5 mM)                                                                        3.5                                                                                   ##STR274##      0.87 (10 mM)                                                                         2.0 579 0.63                                                                              32.4               154 690    1.28 (4 mM)                                                                        3.5                                                                                   ##STR275##      1.14 (8 mM)                                                                          2.5 580 0.54                                                                              30.4               155 690    1.28 (4 mM)                                                                        3.5                                                                                   ##STR276##      1.41 (8 mM)                                                                          2.0 581 0.84                                                                              43.9               156 690    1.28 (4 mM)                                                                        3.5                                                                                   ##STR277##      1.65 (8 mM)                                                                          2.0 582 1.01                                                                              47.8               157 690    1.28 (4 mM)                                                                        3.5                                                                                   ##STR278##      1.80 (8 mM)                                                                          2.5 583 0.78                                                                              37.0               158 691    1.67 (5 mM)                                                                        3.0                                                                                   ##STR279##      0.87 (10 mM)                                                                         2.0 585 0.79                                                                              39.2               159 691    1.34 (4 mM)                                                                        3.0                                                                                   ##STR280##      0.68 (8 mM)                                                                          2.5 586 0.65                                                                              40.5               160 691    1.34 (4 mM)                                                                        3.0                                                                                   ##STR281##      1.14 (8 mM)                                                                          2.5 587 0.77                                                                              42.0               161 691    1.34 (4 mM)                                                                        3.0                                                                                   ##STR282##      1.04 (8 mM)                                                                          2.5 588 0.58                                                                              32.5               162 691    1.34 (4 mM)                                                                        3.0                                                                                   ##STR283##      1.41 (8 mM)                                                                          2.5 589 0.93                                                                              47.3               163 691    1.34 (4 mM)                                                                        3.0                                                                                   ##STR284##      1.68 (8 mM)                                                                          2.5 590 1.07                                                                              50.8               164 691    1.34 (4 mM)                                                                        3.0                                                                                   ##STR285##      2.01 (8 mM)                                                                          2.5 591 1.17                                                                              51.5               165 691    1.34 (4 mM)                                                                        3.0                                                                                   ##STR286##      1.67 (8 mM)                                                                          2.0 592 0.70                                                                              33.4               166 692    1.09 (3 mM)                                                                        4.5                                                                                   ##STR287##      0.53 (6 mM)                                                                          3.0 594 0.64                                                                              49.5               167 692    1.09 (3 mM)                                                                        5.0                                                                                   ##STR288##      0.86 (6 mM)                                                                          2.5 595 0.84                                                                              57.6               168 692    1.09 (3 mM)                                                                        5.0                                                                                   ##STR289##      1.06 (6 mM)                                                                          2.5 596 0.92                                                                              59.0               169 692    1.09 (3 mM)                                                                        5.0                                                                                   ##STR290##      1.24 (6 mM)                                                                          2.5 597 0.93                                                                              56.4               170 692    1.09 (3 mM)                                                                        4.5                                                                                   ##STR291##      1.25 (6 mM)                                                                          2.5 598 0.83                                                                              50.1               171 693    1.17 (3 mM)                                                                        5.0                                                                                   ##STR292##      0.86 (6 mM)                                                                          2.5 600 0.74                                                                              48.0               172 693    1.17 (3 mM)                                                                        5.0                                                                                   ##STR293##      1.06 (6 mM)                                                                          2.5 601 0.84                                                                              51.1               173 693    1.17 (3 mM)                                                                        5.0                                                                                   ##STR294##      1.17 (6 mM)                                                                          2.5 602 0.93                                                                              54.8               174 693    1.17 (3 mM)                                                                        5.0                                                                                   ##STR295##      1.35 (6 mM)                                                                          2.5 603 0.92                                                                              51.4               175 693    1.17 (3 mM)                                                                        5.0                                                                                   ##STR296##      1.51 (6 mM)                                                                          2.5 604 0.65                                                                              34.7               177 694    1.26 (3 mM)                                                                        4.5                                                                                   ##STR297##      0.86 (6 mM)                                                                          2.5 607 0.86                                                                              52.9               178 694    1.26 (3 mM)                                                                        5.0                                                                                   ##STR298##      1.06 (6 mM)                                                                          2.0 608 0.88                                                                              50.9               179 694    1.26 (3 mM)                                                                        4.5                                                                                   ##STR299##      1.32 (6 mM)                                                                          2.5 609 0.95                                                                              51.1               180 685    1.25 (5 mM)                                                                        6.0                                                                                   ##STR300##      1.42 (10 mM)                                                                         5.0 817 1.10                                                                              59.0               181 689    0.77 (2.5 mM)                                                                      5.5                                                                                   ##STR301##      1.60 (12.3 mM)                                                                       5.0 830 0.45                                                                              43.1               182 685    1.18 (4.7 mM)                                                                      6.5                                                                                   ##STR302##      0.85 (10 mM)                                                                         5.0 837 0.89                                                                              56.3               183 689    0.77 (2.5 mM)                                                                      6.0                                                                                   ##STR303##      0.43 (5 mM)                                                                          6.0 839 0.61                                                                              65.1               184 685    1.25 (5 mM)                                                                        5.0    HNEt.sub.2       1.46 (20 mM)                                                                         24  850 0.38                                                                              25.0               185 689    0.77 (2.5 mM)                                                                      7.0    HNEt.sub.2       0.73 (10 mM)                                                                         24  851 0.47                                                                              52.1               __________________________________________________________________________

                                      TABLE 25                                    __________________________________________________________________________    NMR spectrum, Mass spectrum and Rf-value on silica-gel layer                  chromatography                                                                Comp. No.                                                                           NMR (CDCl.sub.3, inner standard TMS) ppm                                                                         MASS Rf                              __________________________________________________________________________    034   2.34 (3H, s), 2.40 (3H, s), 2.46 (3H, s), 3.76 (3H, s), 4.89 (2H,             s)                                 211                                  035   1.53 (3H, d, J=6.9), 2.28 (3H, s), 2.34 (3H× 2, s), 3.65 (3H,           s), 5.17                           225                                        (1H, q, J=6.9)                                                          036   2.36 (3H, s), 2.41 (3H, s), 2.51 (3H, s), 3.70 (3H, s), 6.11 (1H,             s),                                287                                        7.3-7.6 (5H, m)                                                         037   2.30 (3H, s), 2.35 (6H, s), 4.83 (2H, s)                                                                         197                                  038   1.66 (2H, d, J=7.1), 2.32 (3H, s), 2.38 (3H, s), 2.45 (3H, s),                                                   2117                                       (1H, q, J=7.1)                                                          039   2.33 (3H, s), 2.35 (3H, s), 2.38 (3H, s), 6.05 (1H, s), 7.3-7.6               (5H, m)                            273                                  066   2.32 (3H, s), 2.35 (3H, s), 2.39 (3H, s), 2.46 (3H, s), 2.3-2.5               (4H, m)                            279, 179                             067   1.5-1.7 (3H×2), 2.35 (3H, s), 2.39 (3H, s), 2.47 (3H, s),               3.3-3.7                            263, 179                                   (4H, m), 4.99 (2H, s)                                                   068   2.35 (3H, s), 2.39 (3H, s), 2.46 (3H, s), 2.2-2.7 (6H, m),                                                       309, 179                                   (4H, m), 4.99 (2H, s)                                                   069   2.37 (3H, s), 2.41 (3H, s), 2.45 (3H, s), 3.3-3.6 (2H, m), 3.75               (2H, t,                            240, 179                                   J≈4.7), 4.84 (2H, s), 6.86 (1H, bs)                             070   2.35 (3H×2, s), 2.40 (3H×2, s), 2.47 (3H×2, s),             3.6 (8H, bs), 5.02                 443, 180                                   (4H, s)                            179                                  071   2.21 (3H×2, s), 2.38 (3H, s), 2.42 (3H, s), 2.47 (3H, s),               3.1-3.5 (4H,                       267                                        m), 4.83 (2H, s), 7.0 (1H, bs)                                          072   2.37 (3H, s), 2.42 (3H, s), 2.48 (3H, s) 3.07 (2H, t,                         J≈6.1), 3.54               332, 179                                   (2H, t, J≈6.1), 79(2H, s), 6.8 (1H, bs), 7.0-7.4 (5H, m)        073   2.38 (3H, s), 2.42 (3H, s), 2.51 (3H, s), 2.3-2.6 (6H, m), 3.42               (2H, q,                            309, 240                                   J≈5.7), 3.5-3.8 (4H, m), 4.84 (2H, s)                                                                    179                                  074   1.3-1.7 (6H, m), 2.38 (3H, s), 2.42 (3H, s), 2.50 (3H, s),                                                       307, 240                                   (6H, m), 3.41 (2H, sext, J≈5.6), 3.76 (1H, t,                         J≈5.6), 4.84 (2H, s)       179                                  075   2.36 (3H, s), 2.40 (3H, s), 2.47 (3H, s), 3.4-3.8 (8H, m), 4.99               (2H, s)                            266, 179                             076   2.42 (3H, s), 2.46 (3H, s), 2.50 (3H, s), 2.3-2.6 (12H, m), 3.40              (2H.                               352                                        q, J≈6), 3.62 (2H, t, J≈5.2), 4.84 (2H, s)              103   2.38 (3H, s), 2.42 (3H, s), 2.51 (3H, s), 2.3-2.6 (6H, m),                                                       308-2.9                                    (4H, m), 3.41 (2H, q, J≈5.5), 4.84 (2H, s), 7.0 (1H, bs)        105   2.26 (3H, s), 2.38 (3H, s), 2.43 (3H, s), 2.51 (3H, s), 3.2-3.5               (4H,                               322, 113                                   m), 4.84 (2H, s), 7.0 (1H, bs)                                          135   2.37 (3H, s), 2.43 (3H, s), 2.51 (3H, s), 2.2-2.6 (10H, m),                                                      434, 432                                   (2H, m), 3.42 (2H, s), 4.83 (2H, s), 7.26 (4H, s)                                                                223, 125                             136   2.26 (3H, s), 2.38 (3H, s), 2.50 (3H, s), 2.2-2.6 (10H, m),                                                      398, 304                                   (2H, m), 3.48 (2H, s), 4.83 (2H, s), 7.30 (5H, s)                                                                189                                  137   2.38 (3H, s), 2.44 (3H, s), 2.46 (3H, s), 2.3-2.6 (10H, m)                                                       434, 432                                   (2H, m), 3.60 (2H, s), 4.84 (2H, s), 6.9-7.5 (4H,                                                                223, 125                             341   1.33 (3H, t, J=7.4), 1.74 (2H, br. s), 2.35 (3H, s), 2.40 (3H, s),            2.3-                               399                                        2.6 (4H, m), 2.92 (2H, q, J=7.4), 3.2-3.5 (2H, m), 3.5-3.7 (4H, m),           6.44                                                                          (1H, s), 7.0 (1H, br. s), 7.2-7.7 (5H, m)                               342   1.33 (3H, t, J=7.4), 1.77 (4H, br. s), 2.34 (3H, s), 2.40 (3H, s),            2.3-                               488, 189                                   2.6 (6H, m), 2.91 (2H, q, J=7.4), 3.2-3.5 (2H, m), 3.49 (2H, s),              6.42                                                                          (1H, s), 7.0-7.7 (11H, m)                                               343   1.33 (3H, t, J=7.4), 1.6 (4H, br. s), 2.34 (3H, s), 2.40 (3H, s),             2.2-                               524, 522                                   2.8 (6H, m), 2.92 (2H, q, J=7.4), 3.2-3.5 (2H, m), 3.43 (2H, s),              6.42                               223                                        (1H, s), 7.26 (1H, s), 7.2-7.6 (5H, m)                                  344   1.34 (3H, t, J=7.4), 1.66 (4H, br. s), 2.35 (3H, s), 2.40 (3H, s),            2.2-                               533, 234                                   2.6 (6H, m), 2.92 (2H, q, J=7.4), 3.2-3.5 (2H, m), 3.56 (2H, s),              6.43                                                                          (1H, s), 7.0 (1H, br. s), 7.2-7.7 (7H, m), 8.18 (2H, d, J=8.8)          345   1.34 (3H, t, J=7.4), 1.90 (2H, br. s), 2.34 (3H, s), 2.41 (3H, s),            2.2-                               560, 558                                   2.6 (8H, m), 2.92 (2H, q, J=7.4), 3.2-3.5 (2H, m), 3.55 (2H, s),              6.43                               556, 258                                   (1H, s), 7.0-7.7 (9H, m)           256                                  346   1.34 (3H, t, J=7.4), 1.73 (2H, br. s), 2.35 (3H, s), 2.38 (3H, s),            2.3-                               474, 330                                   2.6 (6H, m), 2.88 (2H, q, J=7.4), 3.0-3.2 (2H, m), 3.3-3.5 (2H,                                                  175                                        6.45 (1H, s), 6.7-7.7 (10H, m)                                          347   1.31 (3H, t, J=7.4, 1.6-2.1 (4H, m), 2.34 (3H, s), 2.40 (3H, s),              2.2-                               521, 520                                   2.8 (8H, m), 2.90 (2H, q, J=7.4), 3.2-3.5 (2H, m), 3.54 (2H, s),              6.43                               221                                        (1H, s), 6.8-7.7 (10H, m)                                               348   1.31 (3H, t, J=7.4), 1.6-2.1 (2H, m), 2.34 (3H, s), 2.40 (3H, s),             2.4-                               538, 536                                   2.8 (12H, m), 3.1-3.5 (2H, m), 3.54 (2H, s), 6.43 (1H, s), 7.26               (4H,                               239, 237                                   s), 7.2-7.6 (5H, m)                                                     376   1.23 (3H×2, t, J≈7.6), 1.4-2.2 (8H, m), 2.2-3.6 (10H,           m), 4.21 (4H,                      487, 174                                                                           0.44                                  s), 4.83 (2H, s), 6.51 (1H, br. s), 7.0-7.4 (10H, m)                    377   1.22 (3H, t, J≈7.6), 1.26 (3H, t, J=7.6), 1.6-2.0 (2H, m),            2.2-2.5                            520, 207                                                                           0.38                                  (8H, m), 2.69 (2H, q, J≈7.6), 2.77 (2H, q, J≈7.6),            3.1-3.6 (2H, m)                                                               3.36 (2H, s), 4.18 (2H, s), 4.81 (2H, s), 6.4 (1H, br. s), 6.8-7.4            (9H,                                                                          m)                                                                      379   1.22 (3H, t, J≈7.6), 1.26 (3H, t, J=7.6), 1.6-2.0 (2H, m),            2.2-3.0                            538, 536                                                                           0.40                                  (14H, m), 3.0-3.6 (2H, m), 3.36 (2H, s), 4.18 (2H, s), 4.81 (2H,                                                 225,223                                    6.4 (1H, br. s), 7.0-7.4 (9H, m)                                        381   1.23 (3H×2, t, J≈7.6), 1.6-1.8 (2H, m), 2.2-3.0 (14H,           m), 3.0-3.5                        524, 522                                                                           0.62                                  (2H, m), 4.19 (2H, s), 4.84 (2H, s), 6.51 (1H, br. s), 6.8-7.4 (9H,           m)                                                                      382   1.22 (3H, t, J≈7.6), 1.25 (3H×2, t, J≈7.6),             1.4-2.0 (2H, m), 2.2-              552, 550                                                                           0.37                                  3.0 (14H, m), 3.0-3.4 (2H, m), 3.50 (2H, s), 4.07 (2H, s), 4.81               (2H,                               343, 237                                   s), 6.4 (1H, br. s), 7.0-7.4 (9H, m)                                    491   1.23 (3H, t, J≈7.6), 2.32 (3H×2), 2.3-3.0 (8H, m),              3.6- 3.8 (4H, m),                  266, 114                                                                           0.33                                  4.0-4.3 (2H, m)                                                         492   1.23 (3H, t, J≈7.4), 1.3-2.0 (6H, m), 2.31 (3H, s), 2.33              (3H, s), 2.5-                      264, 179                                                                           0.28                                  3.0 (8H, m), 4.2-4.5 (2H, m)                                            493   0.9-1.2 (3H, m), 1.23 (3H, t, J≈7.4), 1.3-2.0 (5H, m), 2.31           (3H, s),                           278, 111                                                                           0.29                                  2.33 (3H, s), 2.5-3.0 (8H, m), 4.2-4.5 (2H, m)                          494   1.23 (3H, t, J≈7.4), 2.30 (3H×2, s), 2.31 (3H, s),              2.3-3.0 (12H, m),                  279, 113                                                                           0.15                                  4.0-4.3 (2H, m)                                                         495   1.22 (3H, t, J≈7.4), 2.31 (3H×2, s), 2.3-3.0 (14H,              m), 3.62 (2H, t,                   309, 143                                                                           0.06                                  J=5.4), 4.0-4.3 (2H, m)                                                 496   1.23 (3H, t, J≈7.4), 2.31 (3H×2, s), 2.3-3.0 (14H,              m), 3.5-3.8 (6H,                   353, 187                                                                           0.11                                  m), 4.0-4.3 (3H, m)                                                     497   1.22 (3H, t, J≈7.4), 2.31 (3H×2, s), 2.3-3.0 (12H,              m), 3.52 (2H, s),                  355, 189                                                                           0.38                                  4.0-4.3 (2H, m), 7.30 (5H, s)                                           498   1.22 (3H, t, J≈7.4), 2.31 (3H×2, s), 2.3-3.0 (12H,              m), 3.48 (2H, s),                  391, 389                                                                           0.36                                  4.0-4.3 (2H, m), 7.29 (4H, s)      223                                  499   1.22 (3H, t, J≈7.4), 2.31 (3H×2, s), 2.3-3.0 (12H,              m), 3.46 (2H, s),                  385, 219                                                                           0.33                                  3.79 (3H, s), 4.0-4.3 (2H, m), 6.84 (2H, d, J=8.6), 7.22 (2H, d, J=           8.6)                                                                    500   1.22 (3H, t, J≈7.4), 2.31 (3H×2, s), 2.3-3.0 (12H,              m), 3.47 (2H, s),                  373, 207                                                                           0.35                                  4.0-4.3 (2H, m), 6.8-7.4 (4H, m)                                        501   1.22 (3H, t, J≈7.4), 2.31 (3H, s), 2.33 (3H, s), 2.3-3.0              (12H, m),                          400, 234                                                                           0.39                                  3.59 (2H, s), 4.0-4.2 (2H, m), 7.50 (2H, d, J=8.8), 8.17 (2H, d, J=           8.8)                                                                    502   1.23 (3H, t, J≈7.4), 1.6-2.0 (2H, m), 2.31 (3H, s), 2.33              (3H, s), 2.5-                      414, 248                                                                           0.28                                  3.0 (12H, m), 3.72 (2H, s), 4.0-4.3 (2H, m), 7.51 (2H, d,                     J≈8.8),                                                               8.19 (2H, d, J≈8.8)                                             503   1.23 (3H, t, J≈7.4), 1.6-2.0 (2H, m), 2.31 (3H×2, s),           2.5-3.0 (12H,                      387  0.20                                  m), 3.60 (2H, s), 4.0-4.3 (2H, m), 6.8-7.4 (4H, m)                      504   1.22 (3H, t, J≈7.4), 1.6-2.0 (2H, m), 2.31 (3H×2,s),            2.5-3.0 (12H,                      405, 403                                                                           0.23                                  m), 7.27 (4H, s)                   237                                  511   2.31 (3H×2, s), 2.4-2.7 (6H, m), 3.6-3.8 (4H, m), 4.0-4.3               (2H, s),                           328, 114                                                                           0.41                                  7.1-7.5 (5H, m)                                                         512   2.30 (3H×2, s), 2.3-2.7 (10H, m), 3.51 (2H, s), 4.0-4.2 (2H,            m),                                417, 202                                                                           0.37                                  4.08 (2H, s), 7.1-7.5 (10H, m)     189                                  516   1.6-2.0 (2H, m), 2.30 (3H×2,s), 2.5-3.0 (10H, m), 3.58 (2H,             s), 3.9-                           467, 465                                                                           0.24                                  4.2 (2H, m), 4.08 (2H, s), 7.1-7.5 (10H, m)                                                                      251, 237                             536   2.30 (3H, s), 2.34 (3H, s), 2.41 (3H, s), 2.4-2.7 (6H, m),                                                       252, 101                                                                           0.30                                  (4H, m), 4.0-4.3 (2H, m)                                                537   1.2-1.8 (6H, m), 2.30 (3H, s), 2.36 (3H, s), 2.41 (3H, s),                                                       250, 111                                                                           0.20                                  (6H, m), 4.1-4.3 (2H, m)                                                538   2.29 (3H, s), 2.32 (3H, s), 2.40 (3H, s), 2.3-2.8 (10H, m), 3.52              (2H,                               341, 189                                                                           0.27                                  s), 4.0-4.3 (2H, m), 7.30 (5H, s)                                       539   2.30 (3H, s), 2.32 (3H, s), 2.41 (3H, s), 2.3-2.8 (10H, m), 3.47              (2H,                               377, 375                                                                           0.27                                  s), 4.0-4.3 (2H, m), 7.26 (4H, s)  223                                  540   2.30 (3H, s), 2.33 (3H, s), 2.41 (3H, s), 2.4-2.8 (10H, m), 3.48              (2H,                               359, 220                                                                           0.20                                  s), 4.0-4.3 (2H, m), 6.8-7.4 (4H, m)                                                                             207                                  541   1.6-2.0 (2H, m), 2.30 (3H, s), 2.32 (3H, s), 2.41 (3H, s),                                                       391, 389                                                                           0.17                                  (10H, m), 3.60 (2H, s), 4.0-4.3 (2H, m), 7.26 (4H,                                                               237, 165                             544   1.20 (3H×2, d, J=6.8), 2.32 (3H×× 2, s), 2.4-2.8            (6H, m), 3.42 (1H,                 280, 114                                                                           0.33                                  sept, J=6.8), 3.5-3.8 (4H, m), 4.0-4.3 (2H, m)                          546   1.20 (3H×2, d, J=6.8), 2.30 (3H×2, s), 2.2-2.8 (10H,              m), 3.42 (1H,                      405, 403                                                                           0.33                                  sept, J=6.8), 3.47 (2H, s), 3.9-4.2 (2H, m), 7.27 (4H, s)               547   1.20 (3H×2, d, J=6.8), 1.6-2.0 (2H, m), 2.30 (3H×2, s),           2.5-3.0                            419, 417                                                                           0.23                                  (10H, m), 3.42 (1H, sept, J=6.8), 3.60 (2H, s), 3.9-4.2 (2H,                                                     237                                        7.27 (4H, s)                                                            550   1.0-1.3 (12H, m), 1.3-1.8 (6H, m), 2.3-2.8 (10H, m), 3.42 (1H,                sept,                              306, 112                                                                           0.30                                  J=6.8), 4.0-4.3 (2H, m)                                                 551   0.91 (3H, t, J≈6), 1.20 (3H×2, d, J=6.8), 1.21                  (3H×2, d, J=7.6), 1.2-       363, 155                                                                           0.25                                  1.6 (4H, m), 2.3-2.8 (16H, m), 2.42 (1H, sept, J=6.8), 4.0-4.2 (2H,           m)                                                                      552   1.20 (3H×2, d, J=6.8), 1.21 (3H×2, d, J=7.6), 2.3-2.8             (14H, m),                          397, 189                                                                           0.35                                  3.42 (1H, sept, J=6.8), 3.51 (2H, s), 4.0-4.2 (2H, m), 7.30 (5H, s)     553   1.20 (3H×2, d, J=6.8), 1.21 (3H×2, d, J=7.6), 1.6-2.0             (2H, m), 2.4-                      441, 233                                                                           0.21                                  3.0 (14H, m), 3.42 (1H, sept, J=6.8), 3.59 (2H, s), 3.80 (3H, s),             3.9-                                                                          4.2 (2H, m), 6.84 (2H, d, J=8.8), 7.24 (2H, d, J=8.8)                   556   0.94 (3H×2, d, J=6.7), 1.20 (3H, t, J=7.6), 1.21 (3H, t,                J=7.6), 2.0-                       411, 189                                                                           0.32                                  2.4 (1H, m), 2.4-3.0 (16H, m), 3.53 (2H, s), 4.0-4.3 (2H, m), 7.30            (5H, s)                                                                 558   0.94 (3H×2, d, J=6.7), 1.20 (3H, t, J=7.6), 1.21 (3H, t,                J=7.6), 1.6-                       455, 246                                                                           0.17                                  2.0 (2H, m), 2.0-2.4 (1H, m), 2.4-3.0 (16H, m), 3.60 (2H, s),                                                    1210                                       (3H, s), 3.9-4.2 (2H, m), 6.84 (2H, d, J=8.6), 7.25 (2H, d, J=8.6)      648   2.32 (3H, s), 2.35 (3H×2, s), 3.3-3.5 (2H, m), 4.2-4.4 (2H,             m), 4.99                           304, 302                                   (2H, s), 8.0 (1H, br. s)           222, 179                             649   2.38 (3H, s), 2.43 (3H, s), 2.48 (3H, s), 3.6-3.8 (4H, m), 4.85               (2H,                               260, 258                                   s), 6.8 (1H, br. s)                                                     650   0.7-2.0 (10H, m), 2.1-2.5 (1H, m), 2.37 (3H, s), 2.42 (3H, s),                                                   3218                                       (3H, s), 2.81 (2H, t, J=5.8), 3.2-3.5 (3H, m), 4.84 (2H, s), 7.1              (1H, br. s)                                                             651   1.29 (3H, t, J≈7), 2.36 (3H, s), 2.41 (3H, s), 2.87 (2H, q,           J≈7), 3.69                 301, 121                                   (3H, s), 6.14 (1H, s), 7.3-7.7 (5H, m)                                  652   1.22 (3H, t, J≈7.6), 2.31 (3H, s), 2.37 (3H, s), 2.83 (2H,            q, J≈7.6),                 287                                        5.65 (1H, br. s), 6.14 (1H, s), 7.2-7.6 (5H, m)                         653   1.22 (3H/2, t, J≈7.4), 1.27 (3H/2, t, J≈7.4), 2.72            (1H, q, J=7.4),                    364, 362                                   2.80 (1H, q, J≈7.4), 3.2-3.5 (4H, m), 4.17 (2H, s), 4.81              (2H, s), 6.9                       241, 146                                   (1H, br. s), 7.0-7.4 (5H, m)                                            654   1.19 (3H, t, J=5.7), 1.23 (3H, t, J=5.7), 2.65 (2H, q, J=5.7),                                                   3153                                       (2H, q, J=5.7), 3.73 (3H, s), 4.16 (2H, s), 4.85 (2H, s), 7.0-7.5             (5H,                                                                          m)                                                                      655   1.19 (3H, t, J=7.6), 1.21 (3H, t, J=7.6), 2.65 (2H, q, J=7.6),                                                   3015                                       (2H, q, J=7.6), 4.16 (2H, s), 4.88 (2H, s), 6.98 (1H, br. s),                 7.0-7.4                                                                       (5H, m)                                                                 656   1.22 (3H, t, J=7.4), 1.27 (3H, t, J=7.4), 2.72 (2H, q, J=7.4),                                                   364, 362                                   (2H, q, J=7.4), 3.2-3.5 (4H, m), 4.17 (2H, s), 4.81 (2H, s), 6.91             (1H,                               241, 146                                   br. s), 7.0-7.4 (5H, m)                                                 657   1.23 (3H, t, J≈7.6), 1.26 (3H, t, J≈7.6), 1.6-1.8             (2H, m), 2.34                      413, 102                                                                           0.50                                  (2H × 2, J≈4.7), 2.70 (2H, q, J≈7.6), 2.78              (2H, q, J≈7.6), 3.0-3.4                                               (2H, m), 3.4-3.6 (4H, m), 4.18 (2H, s), 4.83 (2H, s), 6.31 (1H, br.           s),                                                                           7.0-7.4 (5H, m)                                                         658   1.23 (3H, t, J=7.6), 1.4-2.0 (2H, m), 2.2-3.6 (10H, m), 4.21 (2H,             s),                                487, 174                                                                           0.44                                  4.83 (2H, s), 6.51 (1H, br. s), 70.-7.4 (10H, m)                        662   1.23 (3H, t, J≈7.6), 2.39 (3H×2, s), 2.83 (2H, q,               J≈7.4), 3.75 (3H, s)       225                                        4.88 (2H, s)                                                            663   2.33 (3H, s), 2.41 (3H, s), 3.73 (3H, s), 4.15 (2H, s), 4.87 (2H,             s),                                287                                        7.0-7.4 (5H, m)                                                         664   1.27 (3H × 2, d, J=6.8), 2.32 (3H, s), 2.40 (3H, s), 3.34               (1H, sept, J =                     239                                        6.8), 3.75 (3H, s), 4.90 (2H, s)                                        665   1.23 (3H, t, J=7.6), 1.24 (3H, t, J=7.6), 1.28 (3H×2, d,                J=6.8),                            267  0.89                                  2.65 (2H, q, J=7.6), 2.73 (2H, q, J=7.6), 3.34 (1H, sept, J=6.8),             3.74 (3H, s), 4.87 (2H, s)                                              666   0.94 (3H×2, d, J=6.7), 1.20 (3H, t, J≈7.3), 1.21 (3H,           t, J≈7.3), 2.18            281  0.68                                  (1H, sept, J=7.3), 2.5-2.9 (6H, m), 3.74 (3H, s), 4.86 (2H, s)          679   2.38 (3H, s), 2.41 (3H×2, s), 3.64 (1H, t, J≈5.5),              3.8- 4.1 (3H, m),                  183  0.59                                  4.4-4.6 (2H, m)                                                         680   1.23 (3H, t, J≈7.4), 2.32 (3H×2, s), 2.78 (2H, q,               J≈7.4), 3.8-4.1            197  0.64                                  (3H, m), 4.4-4.6 (2H, m)                                                681   2.38 (3H, s), 2.45 (3H, s), 2.6-2.8 (1H, br.m), 3.7-3.9 (2H, m),              4.11                               259  0.91                                  (2H, s), 4.3-4.5 (2H, m), 7.1-7.4 (5H, m)                               682   1.24 (3H×2, d, J≈6.8), 2.37 (3H, s), 2.42 (3H, s),              3.29 (1H, sept, J≈         211  0.57                                  6.8), 3.6-4.0 (2H, m), 4.3-4.5 (2H, m)                                  683   1.1-1.4 (12H, m), 2.70 (2H, q, J=7.6), 3.30 (1H, sept, J=6.8),                                                   239- 0.63                                  4.1 (3H, m), 4.4-4.6 (2H, m)                                            684   0.93 (3H×2, d, J≈6.7), 1.20 (3H, t, J≈7.3),             1.26 (3H, t, J≈7.3),       253  0.71                                  2.13 (1H, sept, J≈7.3), 2.6-2.9 (6H, m), 3.67 (1H, t,                 J≈5.3), 3.8-                                                          4.1 (3H, m), 4.4-4.6 (2H, m)                                            697   0.91 (3H, t, J≈6), 1.20 (3H×2, d, J=6.8), 1.2-1.6               (4H, m), 2.2-2.8                   345  0.18                                  (12H, m), 2.31 (3H×2, q), 3.43 (1H, sept, J=6.8), 4.0- 4.3              (2H, m)                                                                 810   0.91 (3H, t), 1.1-1.6 (4H, m), 2.30 (3H, s), 2.34 (3H, s), 2.41               (3H,                               307  0.26                                  s), 4.15 (2H, t), 2.3-2.7 (12H, m)                                      812   0.91 (3H, t), 1.23 (3H, t), 1.1-1.6 (4H, m), 2.31 (6H, s),                                                       321-2.9                                                                            0.19                                  (14H, m), 4.14 (2H, t)                                                  814   0.91 (3H, t), 1.20 (6H, t), 1.1-1.7 (4H, m), 2.31 (6H, s),                                                       335-2.9                                                                            0.22                                  (12H, m), 3.42 (1H, sept), 4.14 (2H, t)                                 822   2.30 (3H, s), 2.33 (3H, s), 2.41 (3H, s), 2.3-2.7 (12H, m), 3.62              (2H,                               295  0.02                                  t), 4.15 (3H, t)                                                        825   1.20 (6H, d), 2.31 (6H, s), 2.1-2.9 (12H, m), 3.42 (1H, sept),                                                   3232 0.06                                  (2H, t), 4.14 (2H, t)                                                   826   1.21 (6H, d), 1.21 (6H, t), 2.0-2.9 (12H, m), 3.42 (1H, sept),                                                   3512 0.04                                  (2H, t), 4.13 (2H, t)                                                   834   1.20 (6H, d), 1.3-1.8 (6H, m), 2.31 (3H, s), 2.34 (3H, s),                                                       278-2.7                                                                            0.22                                  (6H, m), 3.42 (1H, sept), 4.21 (2H, t)                                  842   1.04 (6H, t), 2.30 (3H, s), 2.35 (3H, s), 2.41 (3H, s), 2.5-2.8               (6H,                               238  0.63                                  m), 4.11 (2H, t)                                                        844   1.04 (6H, t), 1.23 (3H, t), 2.31 (3H, s), 2.34 (3H, s), 2.3-2.9               (8H,                               252  0.46                                  m), 4.11 (2H, t)                                                        846   1.09 (6H, t), 1.20 (6H, d), 2.31 (3H, s), 2.34 (3H, s), 2.4-2.9               (6H,                               266  0.63                                  m), 3.43 (1H, sept), 4.14 (2H, t)                                       848   0.99-1.27 (18H, m), 2.4-2.9 (10H, m), 3.44 (1H, sept), 4.13 (2H,                                                 294  0.27                            __________________________________________________________________________

                                      TABLE 26                                    __________________________________________________________________________    physical properties of 2-hydroxy -3-substituted -5, 6, 7,                     8-tetrahydroquinoxalin                                                         ##STR304##                                                                   R.sub.1 NMR (CDCl.sub.3 φ inner standard TMS) δ ppm                                                          MASS                                 __________________________________________________________________________    Me      78-1.84 (4H, m), 2.42 (3H, s), 2.66 (4H, m), 13.05 (1H, br,                                                    165                                  Et      1.25 (3H, t), 1.7-1.9 (4H, m), 2.5-2.8 (4H, m), 2.80 (2H, q),                 13.06 (1H,                       179                                          br,s)                                                                 Pro     1.00 (4H,t), 1.55 (6H, m), 2.67-2.83 (6H, m), 13.09 (1H, br,                                                   193                                  iso-Pro 1.24 (3H×2, d×2, J=6.8), 1.7-2.0 (4H, m), 2.5-2.8                 (4H, m), 3.41 (1H,               193                                          sept, J=6.8), 12.9 (1H, br, s)                                        Bu      0.94 (3H, t), 1.24-2.00 (8H, m), 2.55-2.85 (6H, m), 12.99 (1H,                br, s)                           207                                  iso-Bu  0.96 (3H×2, d), 1.6-2.0 (4H, m), 2.0-2.4 (1H, m), 2.5-2.8               (6H, m)                          207                                  sec-Bu  0.96 (3H×2, d×2, J=6.7), 1.6-2.2 (5H, m), 2.5-2.8                 (6H, m)                          207                                  (CH.sub.2).sub.4 CH.sub.3                                                             0.90 (3H, t, J=6.3), 1.2-1.5 (4H, m), 1.5-1.9 (6H, m), 2.5-2.9                (6H, m)                          221, 164                             (CH.sub.2).sub.5 CH.sub.3                                                             0.88 (3H, t, J=7.9), 1.1-1.5 (6H, m), 1.5-2.0 (6H, m), 2.4-2.9                (6H, m)                          235                                  (CH.sub.2).sub.6 CH.sub.3                                                             0.88 (3H, t, J=7.4), 1.1-1.5 (8H, m), 1.5-2.0 (6H, m), 2.5-2.9                (6H, m)                          249, 164                             (CH.sub.2).sub.7 CH.sub.3                                                             0.88 (3H, t, J=7.5), 1.1-1.5 (10H, m), 1.5-2.0 (6H, m), 2.5-2.9               (6H, m)                          263                                  (CH.sub.2).sub.8 CH.sub.3                                                             0.88 (3H, t, J=6.2), 1.1-1.5 (12H, m), 1.5-2.0 (6H, m), 2.5-2.8               (6H, m)                          277, 164                             (CH.sub.2).sub.9 CH.sub.3                                                             0.88 (3H, t, J=6), 1.2-2.0 (20H, m), 2.5-2.9 (6H, m), 12.7 (1H,               br, s)                           291                                  (CH.sub.2).sub.11 CH.sub.3                                                            0.88 (3H, t, J=6), 1.1-1.9 (24H, m), 2.4-2.8 (6H,                                                              319, 164                             (CH.sub.2).sub.13 CH.sub.3                                                            0.88 (3H, t, J=6), 1.1-1.9 (28H, m), 2.5-2.8 (6H,                                                              347, 164                             (CH.sub.2).sub.15 CH.sub.3                                                            0.88 (3H, t, J=6), 1.1- 1.9 (32H, m), 2.5-1.8 (6H,                                                             375, 164                             CH.sub.2 Ph                                                                           1.6-2.0 (4H, m), 2.4-2.7 (4H, m), 4.02 (2H, s), 7.0-7.4 (4H,                                                   241                                  CH.sub.2 CH.sub.2 Ph                                                                  1.6-2.0 (4H, m), 2.5-2.8 (4H, m), 3.06 (2H×2, s), 7.1-7.3               (5H, s), 12.9                    255                                          (1H, br, s)                                                           __________________________________________________________________________

                                      TABLE 27                                    __________________________________________________________________________    physical properties of a compound of the present invention                    Comp. No.                                                                           NMR (CDCl.sub.3, inner standard TMS) δ ppm                                                                 MASS Rf                              __________________________________________________________________________    368   1.7-2.0 (4H, m), 2.2-3.0 (14H, m), 3.0-3.6 (2H, m), 3.40 (2H, s),             4.17                               500, 189                                                                           0.45                                  (2H, s), 4.79 (2H, s), 6.4 (1H, br, s), 7.0-7.4 (10H, m)                369   1.6-2.0 (4H, m), 2.1-3.0 (14H, m), 3.0-3.6 (2H, m), 3.34 (2H, s),             3.79                               530, 219                                                                           0.43                                  (3H, s), 4.17 (2H, s), 4.79 (2H, s), 6.4 (1H, br, s), 6.7-7.4 (9H,            m)                                                                      370   1.6-2.0 (4H, m), 2.1-3.0 (14H, m), 3.0-3.6 (2H, m), 3.35 (2H, s),             4.18                               535, 533                                                                           0.4                                   (2H, s), 4.79 (2H, s), 6.3 (1H, br, s), 7.0-7.4 (9H,                                                             223                                  371   1.6-2.0 (4H, m), 2.3-3.0 (10H, m), 3.0-3.4 (6H, m), 4.19 (2H, s),             4.82                               522, 520                                                                           0.48                                  (2H, s), 6.4 (1H, br, s), 6.7-7.4 (9H, m)                                                                        209                                  372   1.5-2.1 (6H, m), 2.3-3.0 (14H, m), 3.0-3.4 (2H, m), 3.51 (2H, s),             4.17                               532, 221                                                                           0.38                                  (2H, s), 4.79 (2H, s), 6.3 (1H, br, s), 6.9-7.4 (9H, m)                 373   1.6-2.1 (2H, m), 2.2-3.0 (10H, m), 3.0-3.4 (4H, m), 4.15 (2H, s),             4.81                               486, 342                                                                           0.49                                  (2H, s), 6.3 (1H, br, s), 6.6-7.4 (10H, m)                                                                       175                                  517   0.93 (3H, t, J≠6.6), 1.2-2.0 (8H, m), 2.4-3.0 (12H, m),                 3.6-3.8 (4H,                       320, 102                                                                           0.42                                  m), 3.9-4.2 (2H, m)                                                     518   0.93 (3H, t, J≠6.6), 1.2-2.0 (8H, m), 2.4-3.0 (16H, m), 3.53            (2H, s),                           4.09, 189                                                                          0.41                                  3.9-4.2 (2H, m), 7.30 (5H, s)                                           519   0.93 (3H, t, J≠6.6), 1.2-2.0 (8H, m), 2.4-3.0 (16H, m), 3.47            (2H, s),                           445, 443                                                                           0.43                                  3.9-4.2 (2H, m), 7.27 (4H, s)      227                                  520   0.93 (3H, t, J≠6.6), 1.2-2.0 (10H, m), 2.4-3.0 (16H, m), 3.60           (2H, s),                           459, 457                                                                           0.29                                  3.9-4.2 (2H, m), 7.27 (4H, s)      237                                  521   0.93 (3H, t, J≠6.6), 1.2-2.0 (8H, m), 2.4-3.0 (12H, m),                 3.0-3.3 (4H,                       395,175                                                                            0.61                                  m), 4.0-4.3 (2H, m), 6.7-7.4 (5H, m)                                    522   0.93 (3H, t, J≠6.6), 1.2-2.0 (8H, m), 2.5-3.0 (12H, m),                 3.2-3.2 (4H,                       425, 205                                                                           0.69                                  m), 3.86 (3H, s), 4.0-4.3 (2H, m), 6.7-7.1 (4H, m)                      559   0.89 (3H, t, J≠6), 1.2-2.0 (10H, m), 2.4-2.9 (12H, m),                  3.6-3.8 (4H,                       334, 102                                                                           0.44                                  m), 3.9-4.2 (2H, m)                                                     560   0.89 (3H, t, J≠6), 0.91 (3H, t, J≠6), 1.2-2.0 (14H, m),           2.2-2.9 (18H,                      389, 155                                                                           0.24                                  m), 3.9-4.2 (2H, m)                                                     561   0.89 (3H, t, J≠6), 1.1-2.0 (10H, m), 2.4-2.9 (16H, m), 3.53             (2H, s),                           423, 189                                                                           0.31                                  3.9-4.2 (2H, m), 7.30 (5H, s)                                           562   0.89 (3H, t, J≠6), 1.1-2.0 (12H, m), 2.4-2.9 (16H, m), 3.61             (2H, s),                           455, 234                                                                           0.19                                  3.9-4.2 (2H, m), 6.8-8.4 (4H, m)   221                                  563   0.89 (3H, t, J≠6), 1.2-2.0 (10H, m), 2.5-2.9 (12H, m),                  3.0-3.2 (4H,                                                                  m), 3.86 (3H, s), 4.0-4.3 (2H, m), 6.7-7.1 (4H, m)                      564   0.87 (3H, t, J≠6), 1.1-2.0 (12H, m), 2.4-2.9 (12H, m),                  3.6-3.8 (4H,                       348, 101                                                                           0.32                                  m), 3.9-4.2 (2H, m)                                                     565   0.87 (3H, t, J≠6), 0.91 (3H, t, J≠6), 1.1-2.0 (16H, m),           2.1-2.9 (18H,                      403, 155                                                                           0.20                                  m), 3.9-4.2 (2H, m)                                                     567   0.87 (3H, t, J≠G), 1.1-2.0 (12H, m), 2.3-2.9 (16H, m), 3.52             (2H, s),                           437, 189                                                                           0.28                                  2.9-4.2 (2H, m), 7.30 (5H, s)                                           568   0.87 (3H, t, J≠6), 1.1-2.0 (12H, m), 2.4-2.9 (16H, m), 3.52             (2H, s),                           473, 471                                                                           0.31                                  3.9-4.2 (2H, m), 7.30 (4H, s)      236, 223                             569   0.87 (3H, t, J≠6), 1.1-2.0 (14H, m), 2.4-3.0 (16H, m), 3.60             (2H, s),                           469, 234                                                                           0.20                                  3.9-4.2 (2H, m), 6.8-7.4 (4H, m)   221                                  570   0.87 (3H, t, J≠6), 1.1-2.0 (12H, m), 2.5-3.0 (12H, m),                  2.9-3.2 (4H,                       453, 218                                                                           0.53                                  3.86 (3H, s), 4.0-4.3 (2H, m), 6.7-7.1 (4H, m)                                                                   205                                  571   0.7-1.0 (6H, m), 1.1-2.0 (18H, m), 2.2-2.9 (18H, m), 3.9-4.2 (2H,             m)                                 417, 155                                                                           0.33                            572   0.87 (3H, t, J≠6), 1.1-2.0 (16H, m), 2.4-2.9 (12H, m),                  3.6-3.8 (4H,                       376  0.58                                  m), 3.9-4.2 (2H, m)                                                     573   0.7-1.0 (6H, m), 1.1-2.0 (20H, m), 2.2-2.9 (18H, m), 3.9-4.2 (2H,             m)                                 431, 155                                                                           0.27                            574   0.87 (3H, t, J≠6), 1.1-2.0 (16H, m), 2.4-2.9 (16H, m), 3.53             (2H, s),                           465, 189                                                                           0.52                                  3.9-4.2 (2H, m), 7.30 (5H, s)                                           575   0.87 (3H, t, J≠6), 1.1-2.0 (16H, m), 2.3-2.9 (16H, m),                  3.9-4.2 (2H,                       501, 499                                                                           0.43                                  m), 7.26 (4H, s)                   223                                  576   0.87 (3H, t, J≠6), 1.1-2.0 (18H, m), 2.5-2.9 (16H, m), 3.59             (2H, s),                           497, 235                                                                           0.24                                  3.9-4.2 (2H, m), 6.8-7.4 (4H, m)   221                                  577   0.88 (3H, t, J≠6), 1.1-2.0 (16H, m), 2.5-2.9 (12H, m),                  3.0-3.3 (4H,                       450, 189                                                                           0.67                                  m), 4.0-4.3 (2H, m), 6.7-7.4 (5H, m)                                                                             175                                  578   0.87 (3H, t, J≠6), 1.1-2.0 (16H, m), 2.5-2.9 (12H, m),                  3.0-3.2 (4H,                       480, 218                                                                           0.55                                  m), 3.77 (3H, s), 4.0-4.2 (2H, m), 6.86 (4H, s)                                                                  205                                  579   0.87 (3H, t, J≠6), 1.0-2.0 (18H, m), 2.4-2.9 (12H, m),                  3.5-3.8 (4H,                       390, 102                                                                           0.39                                  m), 3.9-4.2 (2H, m)                                                     580   0.87 (3H, t, J≠6), 0.91 (3H, t, J≠6), 1.0-2.0 (22H, m),           2.3-2.9 (18H,                      445, 155                                                                           0.29                                  m), 3.9-4.2 (2H, m)                                                     581   0.87 (3H, t, J≠ 6), 1.0-2.0 (18H, m), 2.4-2.9 (16H, m), 3.52            (2H, s),                           479, 202                                                                           0.32                                  3.9-4.2 (2H, m)                    189                                  582   0.87 (3H, t, J≠6), 1.0-2.0 (18H, m), 2.3-2.9 (16H, m), 3.47             (2H, s),                           509, 232                                                                           0.28                                  3.80 (3H, s), 3.9-4.2 (2H, m), 6.84 (2H, d, J=8.8), 7.23 (2H, d,              J=8.8)                             2.19                                 583   0.87 (3H, t, J≠6), 1.0-2.0 (20H, m), 2.4-3.0 (16H, m), 3.59             (2H, s),                           529, 527                                                                           0.39                                  3.9-4.2 (2H, m), 7.26 (4H, s)      250, 237                             584   0.87 (3H, t, J≠6), 1.0-2.0 (18H, m), 2.4-2.9 (12H, m),                  3.0-3.2 (4H,                       501, 499                                                                           0.46                                  m), 3.9-4.2 (2H, m), 6.7-7.3 (4H, m)                                                                             222, 209                             585   0.87 (3H, t, J≠6), 1.0-2.0 (20H, m), 2.4-2.9 (12H, m),                  3.5-3.8 (4H,                       404, 113                                                                           0.37                                  m), 3.9-4.2 (2H, m)                102                                  586   0.87 (3H, t, J≠6), 1.0-2.0 (26H, m), 2.4-2.9 (12H, m),                  4.0-4.3 (4H,                       402, 112                                                                           0.29                                  m)                                                                      587   0.87 (3H, t, J≠6), 0.91 (3H, t, J≠6), 1.0-2.0 (24H, m),           2.2-2.9 (18H,                      459, 155                                                                           0.26                                  m), 3.9-4.2 (2H, m)                125                                  588   0.87 (3H, t, J≠6), 1.0-2.0 (20H, m), 2.3-2.9 (18H, m), 3.62             (2H, t,                            447, 156                                                                           0.12                                  J≠6), 3.9-4.2 (2H, m)        143, 125                             589   0.87 (3H, t, J≠6), 1.0-2.0 (20H, m), 2.4-2.9 (16H, m), 3.52             (2H, s),                           493, 202                                                                           0.37                                  3.9-4.2 (2H, m), 7.30 (5H, s)      189                                  590   0.87 (3H, t, J≠6), 1.0-2.0 (20H, m), 2.3-2.9 (16H, m), 3.52             (2H, s),                           529, 527                                                                           0.41                                  3.9-4.2 (2H, m), 7.26 (4H, s)      236, 223                                                                      125                                  591   0.87 (3H, t, J≠6), 1.0-2.0 (20H, m), 2.3-2.9 (16H, m),                  3.8-4.2 (2H,                       569, 278                                                                           0.66                                  m), 4.22 (1H, s), 7.0-7.6 (10H, m) 167                                  592   0.87 (3H, t, J≠6), 1.0-2.0 (22H, m), 2.4-3.0 (16H, m), 3.60             (2H, s),                           525, 234                                                                           0.27                                  3.9-4.2 (2H, m), 6.8-7.4 (4H, m)   221                                  593   0.87 (3H, t, J≠6), 1.0-2.0 (20H, m), 2.4-2.9 (12H, m),                  2.9-3.2 (4H,                       509, 218                                                                           0.60                                  m), 3.77 (4H, s), 3.9-4.2 (2H, m), 6.6-7.0 (4H, m)                                                               205                                  594   0.88 (3H, t, J≠6), 1.0-2.0 (24H, m), 2.4-3.0 (12H, m),                  3.6-3.8 (4H,                       432, 101                                                                           0.34                                  m), 3.9-4.2 (2H, m)                                                     595   0.88 (3H, t, J≠6), 0.91 (3H, t, J≠6), 1.0-2.0 (28H, m),           2.2-3.0 (18H,                      487, 155                                                                           0.16                                  m), 3.9-4.2 (2H, m)                                                     596   0.88 (3H, t, J≠6), 1.0-2.0 (24H, m), 2.3-2.9 (16H, m), 3.53             (2H, s),                           521, 202                                                                           0.21                                  3.9-4.2 (2H, m), 7.30 (5H, s)      179                                  597   0.88 (3H, t, J≠6), 1.0-2.0 (24H, m),2.4-2.9 (16H, m), 3.47              (2H, s),                           551, 232                                                                           0.21                                  3.79 (3H, s), 3.9-4.2 (2H, m), 6.84 (2H, d, J≠8.6), 7.22 (2H,           d, J≠8.6)                    219                                  598   0.88 (3H, t, J≠6), 1.0-2.0 (26H, m), 2.4-3.0 (16H, m),                  3.9-4.2 (2H,                       553, 234                                                                           0.15                                  m), 6.8-7.4 (4H, m)                221                                  599   0.88 (3H, t, J≠6), 1.0-2.0 (24H, m), 2.5-2.9 (12H, m),                  2.9-3.2 (4H,                       537, 208                                                                           0.43                                  m), 3.86 (3H, s), 3.9-4.1 (2H, m), 6.7-7.1 (2H, m)                                                               205                                  600   0.88 (3H, t, J≠6), 0.91 (3H, t, J≠6), 1.0-2.0 (32H, m),           2.2-2.9 (18H,                      515, 155                                                                           0.22                                  m), 3.9-4.2 (2H, m)                                                     601   0.88 (3H, t, J≠6), 1.0-2.0 (28H, m), 2.4-2.9 (16H, m), 3.51             (2H, s),                           549, 202                                                                           0.36                                  3.9-4.2 (2H, m), 7.29 (5H, s)      189                                  602   0.88 (3H, t, J≠6), 1.0-2.0 (28H, m), 2.3-2.9 (16H, m), 3.47             (2H, s),                           567, 549                                                                           0.37                                  3.9-4.2 (2H, m), 6.8-7.4 (4H, m)   220, 207                             603   0.88 (3H, t, J≠6), 1.0-2.0 (30H, m), 2.4-3.0 (16H, m), 3.60             (2H, s),                           599, 597                                                                           0.30                                  3.9-4.2 (2H, m), 7.27 (4H, s)      250                                  604   0.88 (3H, t, J≠6), 1.0-2.0 (28H, m), 2.3-2.9 (16H, m),                  3.9-4.2 (2H,                       625, 288                                                                           0.71                                  m), 4.23 (1H, s), 7.0-7.5 (10H, m) 167                                  605   0.88 (3H, t, J≠6), 1.0-2.0 (28H, m), 2.5-3.0 (12H, m),                  2.9-3.2 (4H,                       571, 569                                                                           0.71                                  m), 4.0-4.3 (2H, m), 6.8-7.4 (4H, m)                                                                             222, 209                             606   0.88 (3H, t, J≠6), 1.0-2.0 (28H, m), 2.4-2.9 (12H, m),                  3.5-3.8 (4H,                       488, 113                                                                           0.47                                  m), 3.9-4.2 (2H, m)                                                     607   0.88 (3H, t, J≠6), 0.91 (3H, t, J≠6), 1.0-2.0 (36H, m),           2.1-2.8 (18H,                      543, 168                                                                           0.26                                  m), 3.9-4.2 (2H, m)                155                                  608   0.88 (3H, t, J≠6), 1.0-2.0 (32H, m), 2.3-2.9 (16H, m), 3.51             (2H, s),                           578, 202                                                                           0.35                                  3.9-4.2 (2H, m), 7.29 (5H, s)                                           609   0.88 (3H, t, J≠6), 1.0-2.0 (34H, m), 2.5-2.9 (16H, m), 3.62             (2H, s),                           621, 246                                                                           0.25                                  3.80 (3H, s), 3.9-4.2 (2H, m), 6.84 (2H, d, J=8.6), 7.26 (2H, d,              J=8.6)                             121                                  610   0.88 (3H, t, J≠6), 1.0-2.0 (32H, m), 2.4-2.9 (12H, m),                  2.9-3.2 (4H,                       592, 218                                                                           0.45                                  m), 3.76 (3H, s), 3.9-4.2 (2H, m), 6.6-7.0 (4H, m)                      659   1.7-1.9 (4H, m), 2.6-2.9 (4H, m), 3.73 (3H, s), 4.16 (2H, s), 4.86            (2H,                               313                                        s), 7.0-7.4 (5H, m)                                                     660   1.7-1.9 (4H, m), 2.6-3.0 (4H, m), 4.16 (2H, s), 4.87 (2H, s),                 7.0-7.5                            299                                        (5H, m)                                                                 661   1.7-1.9 (4H, m), 2.6-2.9 (4H, m), 3.2-3.5 (4H, m), 4.17 (2H, s),              4.85                               362, 360                                   (2H, s), 7.0-7.5 (5H, m)                                                667   0.94 (3H, t, J≠7.4), 1.2-2.0 (8H, m), 2.6-3.0 (6H, m), 3.75             (3H, s),                           279  0.89                                  4.88 (2H, s)                                                            668   0.89 (3H, t, J≠6), 1.2-2.0 (10H, m), 2.6-3.0 (6H, m), 3.75              (3H, s),                           293  0.90                                  4.89 (2H, s)                                                            669   0.88 (3H, t, J≠6), 1.2-2.0 (12H, m), 2.6-3.0 (6H, m), 3.75              (3H, s),                           307  0.92                                  4.88 (2H, s)                                                            670   0.88 (3H, t, J≠6), 1.2-2.0 (14H, m), 2.6-3.0 (6H, m), 3.75              (3H, s),                           321  0.93                                  4.89 (2H, s)                                                            671   0.87 (3H, t, J≠6), 1.2-2.0 (16H, m), 2.6-3.0 (6H, m, 3.75               (3H, s),                           335  0.93                                  4.88 (2H, s)                                                            672   0.87 (3H, t, J≠6), 1.1-2.0 (18H, m), 2.6-3.0 (6H, m), 3.75              (3H, s),                           349  0.93                                  4.88 (2H, s)                                                            673   0.87 (3H, t, J≠6), 1.1-2.0 (20H, m), 2.6-3.0 (6H, m), 3.75              (3H, s),                           363  0.94                                  4.88 (2H, s)                                                            674   0.87 (3H, t, J≠6), 1.1-2.0 (24H, m), 2.6-3.0 (6H, m), 3.75              (3H, s),                           391  0.94                                  4.88 (2H, s)                                                            675   0.88 (3H, t, J≠6), 1.0-2.0 (28H, m), 2.6-3.0 (6H, m), 3.75              (3H, s),                           419  0.94                                  4.88 (2H, s)                                                            676   0.88 (3H, t, J≠6), 1.0-2.0 (32H, m), 2.6-3.0 (6H, m), 3.75              (3H, s),                           447  0.95                                  4.88 (2H, s)                                                            677   0.99 (3H, t, J= 7.3), 1.5-2.0 (6H, m), 3.75 (3H, s), 3.89 (2H,                                                   265  0.86                            678   0.86 (3H, t, J=7.4), 1.25 (2H, d, J=7.8), 1.6-2.0 (6H, m),                                                       279-2.9                                                                            0.88                                  (4H, m), 2.9-3.3 (1H, m), 3.74 (3H, s), 4.88 (2H, s)                    685   0.93 (3H, t, J≠6.7), 1.1-2.0 (8H, m), 2.6-3.0 (6H, m),                  3.6-4.1 (3H,                       251  0.66                                  m), 4.4-4.6 (2H, m)                                                     686   0.89 (3H, t, J≠6), 1.2-2.0 (10H, m), 2.6-3.0 (6H, m), 3.7               (1H, br, s),                       265  0.67                                  3.8-4.1 (2H, m), 4.4-4.6 (2H, m)                                        687   0.88 (3H, t, J≠6), 1.0-2.0 (12H, m), 2.6-3.0 (6H, m), 3.7               (1H, br, s),                       279  0.67                                  3.8-4.1 (2H, m), 4.3-4.6 (2H, m)                                        688   0.88 (3H, t, J≠6), 1.2-2.0 (14H, m), 2.6-3.0 (6H, m), 3.7               (1H, br, s),                       293  0.67                                  3.8-4.1 (2H, m), 4.4-4.6 (2H, m)                                        689   0.88 (3H, t, J≠6), 1.1-2.0 (16H, m), 2.6-3.0 (6H, m), 3.7               (1H, br, s),                       307  0.69                                  3.8-4.1 (2H, m), 4.4-4.6 (2H, m)                                        690   0.87 (3H, t, J≠6), 1.0-2.0 (18H, m), 2.6-3.0 (6H, m), 3.7               (1H, br, s),                       321  0.70                                  3.8-4.1 (2H, m), 4.4-4.6 (2H, m)                                        691   0.88 (3H, t, J≠6), 1.1-2.0 (20H, m), 2.6-3.0 (6H, m), 3.7-4.1           (3H, m),                           335  0.72                                  4.4-4.6 (2H, m)                                                         692   0.88 (3H, t, J≠6), 1.0-2.0 (24H, m), 2.6-3.0 (6H, m), 3.7-4.1           (3H, m),                           363  0.78                                  4.4-4.6 (2H, m)                                                         693   0.88 (3H, t, J≠6), 1.0-2.0 (28H, m), 2.5-3.0 (6H, m), 3.7-4.1           (3H, m),                           391  0.81                                  4.4-4.6 (2H, m)                                                         694   0.88 (3H, t, J≠6), 1.0-2.0 (32H, m), 2.6-3.0 (6H, m), 3.7-4.1           (3H, m),                           419  0.81                                  4.3-4.6 (2H, m)                                                         695   0.97 (3H, t, J=7.3), 1.5-2.0 (6H, m), 2.6-3.0 (6H, m), 3.7 (1H, br,           s),                                237  0.54                                  3.8-4.1 (2H, m), 4.4-4.6 (2H, m)                                        696   0.84 (3H, t, J=7.4), 1.21 (3H, d, J≠7), 1.2-2.0 (6H, m),                2.6-2.9 (6H,                       251  0.65                                  m), 2.8-3.3 (1H, m), 3.8-4.1 (3H, m), 4.3-4.5 (2H, m)                   817   0.91 (3H, t), 0.93 (3H, t), 1.1-1.9 (12H, m), 2.0-3.0 (18H, m),               4.08                               375  0.22                                  (2H, t)                                                                 830   0.87 (3H, t), 1.1-1.5 (10H, m), 1.5-2.0 (6H, m), 2.4-2.9 (18H,                                                   419  0.23                                  3.63 (2H, t), 4.09 (2H, t)                                              837   0.93 (3H, t), 1.0-2.0 (14H, m), 2.0-3.0 (12H, m), 4.11 (3H,                                                      318  0.28                            839   0.87 (3H, t), 1.1-2.0 (22H, m), 2.4-2.9 (12H, m), 4.12 (2H,                                                      274  0.30                            850   0.93 (3H, t), 106 (6H, t), 1.1-2.0 (8H, m), 2.4-3.0 (12H, m),                                                    3068 0.69                                  (2H, t)                                                                 851   0.87 (3H, t), 1.04 (6H, t), 1.2-1.5 (10H, m), 1.5-2.0 (6H, m),                2.5-3.0                            362  0.19                                  (12H, m), 4.06 (2H, t)                                                  __________________________________________________________________________

What is claimed is:
 1. A compound of the formula ##STR305## wherein Q is --CO-- or --CH₂ --, R is hydroxyl, lower alkoxy, halogen, -NH-lower alkylene-OH, -NH-lower alkylene-arylthio, -NH-lower alkylene-halogen, ##STR306## in which ##STR307## is dilower alkylamino, cycloalkyl-amino, morpholino, ##STR308## in which R₉ is hydrogen, lower alkyl or aryl, R₁₀ is hydrogen, lower alkyl, hydroxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, aryl or di(aryl)-lower alkyl, m is an integer from 4 to 6, n is 2 or 3, R₁ is alkyl or aryl-lower alkyl, R₂ and R₃ together form tetramethylene, R₄ is hydrogen, lower alkyl or aryl, in which aryl is phenyl which is optionally substituted with a group selected from the group consisting of 1-3 halogen, nitro, lower alkyl and lower alkoxy, or a pharmaceutically acceptable salt thereof.
 2. A compound according to claim 1 of the formula ##STR309## wherein R, R₁ and R₄ are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
 3. A compound according to claim 1 of the formula ##STR310## wherein R and R₁ are as defined in claim 1 or a pharmaceutically acceptable salt thereof.
 4. A compound according to claim 1 of the formula ##STR311## wherein R is hydroxyl, halogen or ##STR312## and R₁ are as defined in claim 1, or a pharmaceutically acceptable salt thereof. 